Increased Incidence Of Fractures Research Articles

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

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.

Association between socioeconomic deprivation and bone health status in the UK biobank cohort participants

SummaryThe effect of deprivation on total bone health status has not been well defined. We examined the relationship between socioeconomic deprivation and poor bone health and falls and we found a significant association. The finding could be beneficial for current public health strategies to minimise disparities in bone health.PurposeSocioeconomic deprivation is associated with many illnesses including increased fracture incidence in older people. However, the effect of deprivation on total bone health status has not been well defined. To examine the relationship between socioeconomic deprivation and poor bone health and falls, we conducted a cross-sectional study using baseline measures from the United Kingdom (UK) Biobank cohort comprising 502,682 participants aged 40–69 years at recruitment during 2006–2010.MethodWe examined four outcomes: 1) low bone mineral density/osteopenia, 2) fall in last year, 3) fracture in the last five years, and 4) fracture from a simple fall in the last five years. To measure socioeconomic deprivation, we used the Townsend index of the participant’s residential postcode.ResultsAt baseline, 29% of participants had low bone density (T-score of heel < -1 standard deviation), 20% reported a fall in the previous year, and 10% reported a fracture in the previous five years. Among participants experiencing a fracture, 60% reported the cause as a simple fall. In the multivariable logistic regression model after controlling for other covariates, the odds of a fall, fracture in the last five years, fractures from simple fall, and osteopenia were respectively 1.46 times (95% confidence interval [CI] 1.42–1.49), 1.26 times (95% CI 1.22–1.30), 1.31 times (95% CI 1.26–1.36) and 1.16 times (95% CI 1.13–1.19) higher for the most deprived compared with the least deprived quantile.ConclusionSocioeconomic deprivation was significantly associated with poor bone health and falls. This research could be beneficial to minimise social disparities in bone health.

Metabolic and Skeletal Characterization of the KK/Ay Mouse Model-A Polygenic Mutation Model of Obese Type 2 Diabetes.

Type 2 diabetes (T2D) increases fracture incidence and fracture-related mortality rates (KK.Cg-Ay/J. The Jackson Laboratory; Available from: https://www.jax.org/strain/002468 ). While numerous mouse models for T2D exist, few effectively stimulate persistent hyperglycemia in both sexes, and even fewer are suitable for bone studies. Commonly used models like db/db and ob/ob have altered leptin pathways, confounding bone-related findings since leptin regulates bone properties (Fajardo et al. in Journal of Bone and Mineral Research 29(5): 1025-1040, 2014). The Yellow Kuo Kondo (KK/Ay) mouse, a polygenic mutation model of T2D, is able to produce a consistent diabetic state in both sexes and addresses the lack of a suitable model of T2D for bone studies. The diabetic state of KK/Ay stems from a mutation in the agouti gene, responsible for coat color in mice. This mutation induces ectopic gene expression across various tissue types, resulting in diabetic mice with yellow fur coats (Moussa and Claycombe in Obesity Research 7(5): 506-514, 1999). Male and female KK/Ay mice exhibited persistent hyperglycemia, defining them as diabetic with blood glucose (BG) levels consistently exceeding 300mg/dL. Notably, male control mice in this study were also diabetic, presenting a significant limitation. Nevertheless, male and female KK/Ay mice showed significantly elevated BG levels, HbA1c, and serum insulin concentration when compared to the non-diabetic female control mice. Early stages of T2D are characterized by hyperglycemia and hyperinsulinemia resulting from cellular insulin resistance, whereas later stages may feature hypoinsulinemia due to β-cell apoptosis (Banday et al. Avicenna Journal of Medicine 10(04): 174-188, 2020 and Klein et al. Cell Metabolism 34(1): 11-20, 2022). The observed hyperglycemia, hyperinsulinemia, and the absence of differences in β-cell mass suggest that KK/Ay mice in this studyare modeling the earlier stages of T2D. While compromised bone microarchitecture was observed in this study, older KK/Ay mice, representing more advanced stages of T2D, might exhibit more pronounced skeletal manifestations. Compared to the control group, the femora of KK/Ay mice had higher cortical area and cortical thickness, and improved trabecular properties which would typically be indicative of greater bone strength. However, KK/Ay mice displayed lower cortical tissue mineral density in both sexes and increased cortical porosity in females. Fracture instability toughness of the femora was lower in KK/Ay mice overall compared to controls. These findings indicate that decreased mechanical integrity noted in the femora of KK/Ay mice was likely due to overall bone quality being compromised.

24-hour Urine Calcium Predicts Reduced Fracture Incidence and Improved BMD After Surgery for Primary Hyperparathyroidism.

Contemporary patients with primary hyperparathyroidism are diagnosed with milder disease than previously. Clinical and biochemical factors predictors with impact on fracture incidence and bone mineral density after surgery have not been firmly established. To investigate predictors of fracture incidence and bone mineral density preoperatively and after surgery for primary hyperparathyroidism (pHPT). Prospectively collected surgical cohort with matched population controls. Data were cross-linked with the Swedish National Patient Register, the Prescribed Drug Register, and the Cause of Death Register. Tertiary referral center. 709 patients with successful parathyroidectomy for pHPT, and 2,112 controls matched on sex, age, and municipality were included in the study. Fracture incidence, absolute change and ≥2.77% increase in bone mineral density of femoral neck, L2-L4 and distal third of radius at 1-year follow-up. Patients with pHPT had an increased fracture incidence before surgery but not after pHPT surgery. Fracture incidence after surgery was inversely related to preoperative 24-hour urine calcium (IRR for the highest tertile 220- mg/d 0.29, CI 95% 0.11-0.73). Serum and 24-hour urine calcium, parathyroid hormone, osteocalcin and adenoma weight were all associated with bone mineral density recovery after surgery. 24-hour urine calcium is the most important biochemical variable to predict a decreased fracture incidence and improved bone mineral density after surgery for pHPT.

Altered Osteoblast Metabolism with Aging Results in Lipid Accumulation and Oxidative Stress Mediated Bone Loss.

Cellular aging is associated with dysfunction of numerous tissues affecting multiple organ systems. A striking example of this is related to age-related bone loss, or osteoporosis, increasing fracture incidence. Interestingly, the two compartments of bone, cortical and cancellous or trabecular, rely on different mechanisms for development and maintenance during 'normal' aging. At a cellular level, the aging process disturbs a multitude of intracellular pathways. In particular, alterations in cellular metabolic functions thereby impacting cellular bioenergetics have been implicated in multiple tissues. Therefore, this study aimed to characterize how metabolic processes were altered in bone forming osteoblasts in aged mice compared to young mice. Metabolic flux analyses demonstrated both stromal cells and mature, matrix secreting osteoblasts from aged mice exhibited mitochondrial dysfunction. This was also accompanied by a lack of adaptability or metabolic flexibility to utilize exogenous substrates compared to osteoblasts cultured from young mice. Additionally, lipid droplets accumulated in both early stromal cells and mature osteoblasts from aged mice, which was further depicted as increased lipid content within the bone cortex of aged mice. Global transcriptomic analysis of the bone further supported these metabolic data as enhanced oxidative stress genes were up-regulated in aged mice, while osteoblast-related genes were down-regulated when compared to the young mice. Collectively, these data suggest that aging results in altered osteoblast metabolic handling of both exogenous and endogenous substrates which could contribute to age-related osteoporosis.

Genetic basis of osteogenesis imperfecta from a single tertiary centre in South Africa

AbstractOsteogenesis imperfecta (OI) is a clinically heterogeneous disorder characterised by skeletal fragility and an increased fracture incidence. It occurs in approximately one in every 15–20,000 births and is known to vary considerably in its severity. This report aimed to use next-generation sequencing (NGS) technology to identify disease genes and causal variants in South African patients with clinical-radiological features of OI. A total of 50 affected individuals were recruited at Tygerberg Hospital’s Medical Genetics clinic. Patients were selected for a gene panel test (n = 39), a single variant test (n = 1) or exome sequencing (ES) (n = 12, 7 singletons, 1 affected duo, and 1 trio), depending on funding eligibility. An in-house genomic bioinformatics pipeline was developed for the ES samples using open-source software and tools. This study’s 100% diagnostic yield was largely attributable to an accurate clinical diagnosis. A causal variant in COL1A1 or COL1A2 was identified in 94% of this patient cohort, which is in line with previous studies. Interestingly, this study was the first to identify the common South African pathogenic FKBP10 variant in a patient of mixed ancestry, adding to what was previously known about this variant in our population. Additionally, a recurrent variant in COL1A2: c.1892G&gt;T was discovered in 27 individuals (25 from three large unrelated families and two further individuals), facilitating the establishment of local testing for this variant in South African patients.

Altered Sox9 and FGF signaling gene expression in Aga2 OI mice negatively affects linear growth.

Osteogenesis imperfecta (OI), or brittle bone disease, is a disorder characterized by bone fragility and increased fracture incidence. All forms of OI also feature short stature, implying an effect on endochondral ossification. Using the Aga2+/- mouse, which has a mutation in type I collagen, we show an affected growth plate primarily due to a shortened proliferative zone. We used single-cell RNA-Seq analysis of tibial and femoral growth plate tissues to understand transcriptional consequences on growth plate cell types. We show that perichondrial cells, which express abundant type I procollagen, and growth plate chondrocytes, which were found to express low amounts of type I procollagen, had ER stress and dysregulation of the same unfolded protein response pathway as previously demonstrated in osteoblasts. Aga2+/- proliferating chondrocytes showed increased FGF and MAPK signaling, findings consistent with accelerated differentiation. There was also increased Sox9 expression throughout the growth plate, which is expected to accelerate early chondrocyte differentiation but reduce late hypertrophic differentiation. These data reveal that mutant type I collagen expression in OI has an impact on the cartilage growth plate. These effects on endochondral ossification indicate that OI is a biologically complex phenotype going beyond its known impacts on bone to negatively affect linear growth.

Trabecular Bone Score in Assessing Bone Mineralization Status in Children with End- Stage Renal Disease: A Promising Tool

Areal-bone mineral density (aBMD) of lumbar-spine dual energy X-ray absorptiometry (DXA) scan is the most frequently used tool in evaluating BMD in pediatric patients, however its size dependency have significant impact on measurements accuracy in children with chronic kidney disease (CKD). This study aimed to evaluate the usefulness of trabecular bone score (TBS) computed during lumbar-spine DXA scan in assessing bone status in children on maintenance hemodialysis (HD). Ninety-three children on HD (aged 9–18 years) were subjected to lumbar-spine DXA-scan to obtain aBMD (g/cm2) and TBS.Z-scores of aBMD for chronological-age (aBMDZ-CA), height-age (aBMDZ-HA), and TBSZ-score were calculated using mean and SD values of 442 healthy controls. aBMD and TBS were significantly lower in short-for-age and normal height-for-age patients compared to the corresponding values of controls (p < 0.05 for all). Degraded vertebral microarchitecture (TBSZ-score < -2) was detected in 48% and 44% of male and female patients respectively. There were no significant differences in median TBSZ-score between short-for-age and normal height-for-age HD patients in male (p = 0.425) and in female (p = 0.316) patients. TBSZ-score correlated significantly with aBMDZ-CA (r = 0.234; p = 0.024) but not with aBMDZ-HA (r = 0.077; p = 0.462). Patients with history of fractures (5 patients only) had significantly lower TBS scores compared to those without fracture history (p = 0.016).Conclusion: TBS is significantly reduced in children on maintenance HD and is associated with increased fracture incidence. TBS has shown to be a promising tool in assessing bone quality (trabecular microarchitecture) in children with CKD being not size-dependent as is a-BMD, for further evaluation of its potential role in therapeutic and follow-up decisions.What is Known:• In children with CKD, bone demineralization starts as early as CKD stage 2, so assessment of bone health is mandatory for follow up and therapeutic decisions.• aBMD of lumbar-spine DXA scan is the most used tool in evaluating BMD in pediatric patients, however its size dependency have significant impact on measurements made in children with CKD.What is New:• TBS is significantly reduced in children on maintenance HD and associated with increased fracture incidence.• TBS has shown to be a promising tool in assessing bone quality (trabecular microarchitecture) in children with CKD being not size-dependent as is a-BMD.

Impaired Functional Status Increases Fracture Incidence in 10-year Follow-Up: The Results from RAC-OST-POL Study

Introduction: The aim of study was to establish the influence of baseline functional status on fracture incidence. Methodology: In a prospective 10-years observation in epidemiological sample of postmenopausal women from RAC-OST-POL Study a thesis that affected functional status enhance fracture incidence was verified. At baseline, data were collected in 978 women at mean age 66.48±7.6 years and after 10 years of follow-up 640 subjects at mean age 75.04±6.95 years remained in the study. Functional status at baseline was established using Stand up and Go test (SAG) and Activity of Daily Living (IADL). Afterwards, annually data on fracture incidence were collected by phone interviews. Results: In the period of observation 190 low-energy fractures in 129 women were noted. The whole group was divided into subgroups: without fracture (n=511), with one fracture (n=91) and those ones who had more than one fracture (n=38). In fractured and unfractured subgroup mean SAG results were 11.36±4.28 and 10.36±2.76, respectively and differed significantly (p<0.01). With increasing number of fractures the SAG time was longer – it was 11.15±4.49 in one fracture subgroup and 11.87±3.73 in multiple fractures subgroup, with both values significantly higher than in no fracture subjects. The mean value of IADL was 23.56±1.60. In 576 (90%) women IADL reached maximal value of 24 points. In the rest of them (n=64) IADL score was between 11 and 23 points. Mean value of IADL in fractured and unfractured subgroup were 23.27±1.97 and 23.64±1.47, respectively and differed significantly (p<0.01). Conclusion: The measures of functional status predict fractures in a prospective observation of representative epidemiological female sample.

Fracture distribution in postmenopausal women: a FRISBEE sub-study.

The epidemiology of fracture sites other than MOFs has been less studied. We examined the incidence of fractures according to their sites in a prospective cohort of postmenopausal Belgian women. Three thousand five hundred sixty postmenopausal women, aged 60-85years old, were recruited from 2007 to 2013 and surveyed yearly (FRISBEE). The number of validated incident fractures was recorded and analyzed in relation to age and the fracture site. One thousand three hundred thirty-six fractures were recorded after a mean follow-up of 9.1years. Seven hundred fifty-six fractures (57%) were MOFs and 580 (43%) non-MOFs, while 813 (61%) were central and 523 (39%) peripheral. The increase of fracture incidence with age differed between fracture sites and was steeper for central than for peripheral fractures. The ratio of MOFs to non-MOFs increased significantly with age, from 1.10 (95% CI: 0.83-1.45) for the 60-69 to 1.69 [1.42-2.01] for the 80-89-year subgroup (P = 0.017). This was also true for central versus peripheral fracture. We differentiated three groups of fracture incidence evolution with age: fractures with a mean increase/decade (compared to the 60-69 age group) of less than 1.5, 1.5-2.0, and 2.0-3.0. The lowest increase was seen for most peripheral fractures, whereas the greatest increase included hip, scapula, pelvis, ribs, and spine fractures. The increase of fracture incidence with age varied widely depending on the fracture site, and the ratio of MOFs to non-MOFs rose significantly with age. Some peripheral fractures, such as the ankle, did not increase significantly with age, suggesting that bone fragility does not play a major role in their occurrence.

Long-term outcomes of adjuvant denosumab in breast cancer: Fracture reduction and survival results from 3,425 patients in the randomised, double-blind, placebo-controlled ABCSG-18 trial.

507 Background: State-of-the-art adjuvant endocrine therapy with aromatase inhibitors (AI) compromises bone health in postmenopausal patients with hormone receptor-positive (HR+) breast cancer, increasing fracture incidence. Adjuvant treatment with the anti-RANK ligand denosumab (Dmab) counteracts these side effects and may improve outcomes. We here report the final long-term outcomes of the ABCSG-18 trial (ClinicalTrials.gov NCT00556374). Methods: In this prospective, double-blind, placebo-controlled, phase 3 trial, 3,425 postmenopausal patients with early HR+ breast cancer on AI therapy were randomised in 58 trial centers between 2006 and 2013 to receive either Dmab 60 mg or placebo s.c. every 6 months (q6m). The primary endpoint was time to first clinical fracture, secondary disease outcome-related endpoints were disease-free survival (DFS), bone-metastasis free survival (BMFS), and overall survival (OS). In addition to the main endpoint analyses reported previously, exploratory long-term follow-up was conducted in ABCSG-18. Main time-to-event analyses were based on stratified Cox models. Sensitivity analyses accounting for treatment cross-over associated with a late Dmab open-label phase, as well as for receiving any anti-resorptive agents were performed. Results: For this final protocol-defined analysis, median follow-up is 8 years (Q1,3: 6, 9.6), and all patients had ended their randomly assigned double-blind treatment (Dmab 60mg s.c. q6m n = 1711; placebo s.c. q6m n = 1709) for a median of 5 years. DFS was improved in the Dmab group versus the placebo group (309 versus 368 DFS events, hazard ratio (HR) 0.83, 95% CI 0.71-0.97, p = 0.016), resulting in an absolute 9-year DFS difference of 3.5% (79.4% vs 75.9%, respectively). When censoring for late cross-over and use of anti-resorptive agents, the DFS difference was confirmed (HR 0.82, p = 0.010). BMFS was improved by 19 per cent (HR 0.81, 95% CI 0.65-1.00, p = 0.047) in the Dmab group, and OS was improved by 20 per cent in the uncensored analysis (127 versus 158 OS events, HR 0.80, 95% CI 0.64-1.01, p = 0.065), and 26 per cent after censoring (HR 0.74, 95% CI 0.58-0.94, p = 0.013). The previously reported marked reduction in clinical fractures persisted even long-term, with 201 fractures in the Dmab and 255 fractures in the placebo group (HR 0.76, 95% CI 0.63-0.92, p = 0.004). No new toxicities for this (low) bone-protective dose of adjuvant Dmab were reported, particularly no ONJ occured.. Conclusions: Adjuvant Dmab 60mg every 6 months during AI therapy is safe, and markedly reduces treatment-induced clinical fractures even in the long-term. DFS, BMFS, and OS are improved in this descriptive final long-term analysis of ABCSG-18. Adjuvant denosumab should be considered for routine clinical use in postmenopausal patients with HR+ breast cancer. Clinical trial information: NCT00556374.

Fracture risk associated with glucocorticoid-induced osteoporosis in Japan.

Glucocorticoid-induced osteoporosis (GIOP) is associated with elevated fracture risk. Practice guidelines have been published to reduce this risk but are insufficiently followed in everyday practice. The objectives of this study were to estimate fracture incidence in patients exposed to oral glucocorticoids and to analyse the impact of glucocorticoid use on fracture incidence. This retrospective cohort study was performed using the Medical Data Vision (MDV) claims database from Japan. All patients aged ≥ 18years initiating oral glucocorticoids and fulfilling Japanese guideline criteria for starting prophylactic osteoporosis treatment between 2009 and 2019 were identified. These were matched to a cohort of unexposed controls using propensity score matching. Fracture incidence in the two cohorts were compared using a Fine-Gray proportional sub-distribution hazard model. 13,090 glucocorticoid-exposed cases were compared to 13,090 unexposed controls. The 1-year fracture rate (all sites) was 9.3[95% CI 8.8-9.8] in cases and 5.8 [5.4-6.2] in controls. One-year vertebral fracture rates were 4.3[4.0-4.7] and 2.3[2.1-2.6] respectively. In the multivariate analysis, the use of glucocorticoids was associated with an increase in the incidence of osteoporotic fractures (hazard ratio: 1.63 [1.51-1.76]). The glucocorticoid-associated risk tended to be higher in subgroups of patients with rheumatoid arthritis, asthma, COPD and in those aged < 65years. Oral glucocorticoid use is associated with an increase in fracture incidence. It is necessary to raise awareness of GIOP and to take public health measures to change the perceptions and behaviour of doctors prescribing glucocorticoids.

FGF23-Klotho Axis and Fractures in Patients Without and With Early CKD: A Case-Cohort Analysis of CARTaGENE.

Whether fibroblast growth factor-23 (FGF23) and α-Klotho are associated with fractures, especially in chronic kidney disease (CKD), remains controversial. We evaluated how FGF23, α-Klotho, and traditional mineral parameters predict fractures in individuals with and without early CKD. We conducted a stratified case-cohort analysis using CARTaGENE, a population-based survey from Quebec, Canada. Individuals aged 40 to 69 years were selected according to outcome and CKD status (non-CKD: eGFR > 60 mL/min/1.73 m2; CKD stage 3: eGFR 30-60 mL/min/1.73 m2]). Baseline levels of c-terminal FGF23 (cFGF23), α-Klotho, parathyroid hormone (PTH), phosphate, and calcium were analyzed for associations with osteoporotic fracture incidence from recruitment (2009-2010) through March 2016. Adjusted Cox models were used, and predictors were treated linearly or flexibly using splines. A total of 312 patients (159 non-CKD; 153 CKD) were included; 98 had ≥ 1 fracture at any site during a median follow up of 70 months. Compared with non-CKD, CKD patients had increased levels of cFGF23 but similar levels of α-Klotho. cFGF23 was linearly associated with increased fracture incidence (adjusted HR = 1.81 [1.71, 1.93] per doubling for all participants). The association of α-Klotho with fracture followed a U-curve (overall P = 0.019) but was attenuated by adjustment for potential mediators (bone mineral density, phosphate, PTH). PTH and phosphate also had U-shaped associations with fracture. Associations were mostly similar between non-CKD and CKD. Adjustment for cFGF23 strongly attenuated the association between CKD status and fractures. cFGF23 is associated linearly with fracture incidence while α-Klotho, PTH, and phosphate levels have a U-shaped association.

Induction of osteogenesis by bone-targeted Notch activation.

Declining bone mass is associated with aging and osteoporosis, a disease characterized by progressive weakening of the skeleton and increased fracture incidence. Growth and lifelong homeostasis of bone rely on interactions between different cell types including vascular cells and mesenchymal stromal cells (MSCs). As these interactions involve Notch signaling, we have explored whether treatment with secreted Notch ligand proteins can enhance osteogenesis in adult mice. We show that a bone-targeting, high affinity version of the ligand Delta-like 4, termed Dll4(E12), induces bone formation in male mice without causing adverse effects in other organs, which are known to rely on intact Notch signaling. Due to lower bone surface and thereby reduced retention of Dll4(E12), the same approach failed to promote osteogenesis in female and ovariectomized mice but strongly enhanced trabecular bone formation in combination with parathyroid hormone. Single cell analysis of stromal cells indicates that Dll4(E12) primarily acts on MSCs and has comparably minor effects on osteoblasts, endothelial cells, or chondrocytes. We propose that activation of Notch signaling by bone-targeted fusion proteins might be therapeutically useful and can avoid detrimental effects in Notch-dependent processes in other organs.

Loss of function of lysosomal acid lipase (LAL) profoundly impacts osteoblastogenesis and increases fracture risk in humans.

Lysosomal acid lipase (LAL) is essential for cholesteryl ester (CE) and triacylglycerol (TAG) hydrolysis in the lysosome. Clinically, an autosomal recessive LIPA mutation causes LAL deficiency (LALD), previously described as Wolman Disease or Cholesteryl Ester Storage Disease (CESD). LAL-D is associated with ectopic lipid accumulation in the liver, small intestine, spleen, adrenal glands, and blood. Considering the importance of unesterified cholesterol and fatty acids in bone metabolism, we hypothesized that LAL is essential for bone formation, and ultimately, skeletal health. To investigate the role of LAL in skeletal homeostasis, we used LAL-deficient (-/-) mice, in vitro osteoblast cultures, and novel clinical data from LAL-D patients. Both male and female LAL-/- mice demonstarted lower trabecular and cortical bone parameters , which translated to reduced biomechanical properties. Further histological analyses revealed that LAL-/- mice had fewer osteoblasts, with no change in osteoclast or marrow adipocyte numbers. In studying the cell-autonomous role of LAL, we observed impaired differentiation of LAL-/- calvarial osteoblasts and in bone marrow stromal cells treated with the LAL inhibitor lalistat. Consistent with LAL's role in other tissues, lalistat resulted in profound lipid puncta accumulation and an altered intracellular lipid profile. Finally, we analyzed a large de-identified national insurance database (i.e. 2016/2017 Optum Clinformatics®) which revealed that adults (≥18years) with CESD (n=3076) had a higher odds ratio (OR=1.21; 95% CI=1.03-1.41) of all-cause fracture at any location compared to adults without CESD (n=13.7M) after adjusting for demographic variables and osteoporosis. These data demonstrate that alterations in LAL have significant clinical implications related to fracture risk and that LAL's modulation of lipid metabolism is a critical for osteoblast function.

Analysis of mechanotransduction dynamics during combined mechanical stimulation and modulation of the extracellular-regulated kinase cascade uncovers hidden information within the signalling noise.

Osteoporosis is a bone disease characterized by brittle bone and increased fracture incidence. With ageing societies worldwide, the disease presents a high burden on health systems. Furthermore, there are limited treatments for osteoporosis with just two anabolic pharmacological agents approved by the US Food and Drug Administration. Healthy bones are believed to be maintained via an intricate relationship between dual biochemical and mechanical (bio-mechanical) stimulations. It is widely considered that osteoporosis emerges as a result of disturbances to said relationship. The mechanotransduction process is key to this balance, and disruption of its dynamics in bone cells plays a role in osteoporosis development. Nonetheless, the exact details and mechanisms that drive and secure the health of bones are still elusive at the cellular and molecular scales. This study examined the dual modulation of mechanical stimulation and mechanotransduction activation dynamics in an osteoblast (OB). The aim was to find patterns of mechanotransduction dynamics demonstrating a significant change that can be mapped to alterations in the OB responses, specifically at the level of gene expression and osteogenic markers such as alkaline phosphatase. This was achieved using a three-dimensional hybrid multiscale computational model simulating mechanotransduction in the OB and its interaction with the extracellular matrix, combined with a numerical analytical technique. The model and the analysis method predict that within the noise of mechanotransduction, owing to modulation of the bio-mechanical stimulus and consequent gene expression, there are unique events that provide signatures for a shift in the system's dynamics. Furthermore, the study uncovered molecular interactions that can be potential drug targets.

4-PBA Treatment Improves Bone Phenotypes in the Aga2 Mouse Model of Osteogenesis Imperfecta.

ABSTRACTOsteogenesis imperfecta (OI) is a genetically heterogenous disorder most often due to heterozygosity for mutations in the type I procollagen genes, COL1A1 or COL1A2. The disorder is characterized by bone fragility leading to increased fracture incidence and long‐bone deformities. Although multiple mechanisms underlie OI, endoplasmic reticulum (ER) stress as a cellular response to defective collagen trafficking is emerging as a contributor to OI pathogenesis. Herein, we used 4‐phenylbutiric acid (4‐PBA), an established chemical chaperone, to determine if treatment of Aga2 +/− mice, a model for moderately severe OI due to a Col1a1 structural mutation, could attenuate the phenotype. In vitro, Aga2 +/− osteoblasts show increased protein kinase RNA‐like endoplasmic reticulum kinase (PERK) activation protein levels, which improved upon treatment with 4‐PBA. The in vivo data demonstrate that a postweaning 5‐week 4‐PBA treatment increased total body length and weight, decreased fracture incidence, increased femoral bone volume fraction (BV/TV), and increased cortical thickness. These findings were associated with in vivo evidence of decreased bone‐derived protein levels of the ER stress markers binding immunoglobulin protein (BiP), CCAAT/−enhancer‐binding protein homologous protein (CHOP), and activating transcription factor 4 (ATF4) as well as increased levels of the autophagosome marker light chain 3A/B (LC3A/B). Genetic ablation of CHOP in Aga2 +/− mice resulted in increased severity of the Aga2 +/− phenotype, suggesting that the reduction in CHOP observed in vitro after treatment is a consequence rather than a cause of reduced ER stress. These findings suggest the potential use of chemical chaperones as an adjunct treatment for forms of OI associated with ER stress. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Incidence of Fractures Before and After Dialysis Initiation.

ABSTRACTFractures are common in dialysis patients, but little is known about the trajectory of incidence rates of different types of fractures before and after dialysis initiation. To address this, we investigated the incidence of major fractures before and after dialysis initiation. We performed a retrospective statistical analysis using the Swedish Renal Registry of 9041 incident dialysis patients (median age 67 years, 67% men) starting dialysis 2005 through 2015 to identify major fractures (hip, spine, humerus, and forearm) occurring during the dialysis transition period from 1 year before until 1 year after dialysis initiation. Using flexible parametric hazard models and the Fine‐Gray model, we estimated adjusted fracture incidence rates and predictors of major fractures. We identified 361 cases with primary diagnosis of major fracture, of which 196 (54%) were hip fractures. The crude incidence rate of major fractures before dialysis initiation was 17 per 1000 patient‐years (n = 157) and after dialysis initiation it was 24 per 1000 patient‐years (n = 204). The adjusted incidence rate of major fractures began to increase 6 months before dialysis initiation, and then stabilized at a higher rate after 1 year. The adjusted incidence rate of hip fractures started to increase sharply 3 months before dialysis initiation, peaked at initiation, and declined thereafter. In contrast, the adjusted incidence rate of non‐hip fractures was stable during the transition period and gradually increased over time. Higher age, female sex, and history of previous major fractures were associated with increased fracture incidence both before and after dialysis initiation. We conclude that the incidence of major fractures, especially hip fractures, start to rise 6 months before initiation of dialysis therapy, indicating that heightened surveillance with implementation of preventive measures to avoid fractures is warranted during the transition period to dialysis. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).