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Geriatric fragility fractures are associated with a human skeletal stem cell defect.

ABSTRACT: Fragility fractures have a limited capacity to regenerate, and impaired fracture healing is a leading cause of morbidity in the elderly. The recent identification of a highly purified bona fide human skeletal stem cell (hSSC) and its committed downstream progenitor cell populations provides an opportunity for understanding the mechanism of age-related compromised fracture healing from the stem cell perspective. In this study, we tested whether hSSCs isolated from geriatric fractures demonstrate intrinsic functional defects that drive impaired healing. Using flow cytometry, we analyzed and isolated hSSCs from callus tissue of five different skeletal sites (n = 61) of patients ranging from 13 to 94 years of age for functional and molecular studies. We observed that fracture-activated amplification of hSSC populations was comparable at all ages. However, functional analysis of isolated stem cells revealed that advanced age significantly correlated with reduced osteochondrogenic potential but was not associated with decreased in vitro clonogenicity. hSSCs derived from women displayed an exacerbated functional decline with age relative to those of aged men. Transcriptomic comparisons revealed downregulation of skeletogenic pathways such as WNT and upregulation of senescence-related pathways in young versus older hSSCs. Strikingly, loss of Sirtuin1 expression played a major role in hSSC dysfunction but re-activation by trans-resveratrol or a small molecule compound restored in vitro differentiation potential. These are the first findings that characterize age-related defects in purified hSSCs from geriatric fractures. Our results provide a foundation for future investigations into the mechanism and reversibility of skeletal stem cell aging in humans.

SUBMITTER: Ambrosi TH

PROVIDER: S-EPMC7370785 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Geriatric fragility fractures are associated with a human skeletal stem cell defect.

Ambrosi Thomas H TH Goodnough L Henry LH Steininger Holly M HM Hoover Malachia Y MY Kim Emiley E Koepke Lauren S LS Marecic Owen O Zhao Liming L Seita Jun J Bishop Julius A JA Gardner Michael J MJ Chan Charles K F CKF

Aging cell 20200614 7

Fragility fractures have a limited capacity to regenerate, and impaired fracture healing is a leading cause of morbidity in the elderly. The recent identification of a highly purified bona fide human skeletal stem cell (hSSC) and its committed downstream progenitor cell populations provides an opportunity for understanding the mechanism of age-related compromised fracture healing from the stem cell perspective. In this study, we tested whether hSSCs isolated from geriatric fractures demonstrate ...[more]

PMID: 32537886

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Project description:INTRODUCTION:Treatment of fractures in the elderly population is a clinical challenge due partly to the presence of comorbidities. In a Geriatric Fracture Centre (GFC), patients are co-managed by a geriatrician in an attempt to improve clinical outcomes and reduce morbidity and mortality. Until now the beneficial effect of orthogeriatric co-management has not been definitively proven. The primary objective of this study is to determine the effect of GFC on predefined major adverse events related to a hip fracture compared to usual care centres (UCC). The secondary objectives include assessments in quality of life, patient-reported outcomes and cost-effectiveness. METHODS AND ANALYSIS:Two hundred and sixty-six elderly patients diagnosedwith hip fracture and planned to be treated with osteosynthesis or endoprosthesis in either a GFC or UCC study site will be recruited, 133 per type of centre. All procedures and management will be done according to the site's standard of care. Study-related visits will be performed at the following time points: preoperative, intraoperative, discharge from the orthopaedic/trauma department, discharge to definite residential status, 12 weeks and 12 months postsurgery. Data collected include demographics, residential status, adverse events, patient-reported outcomes, fall history, costs and resources related to treatment. The risk of major adverse events at 12 months will be calculated for each centre type; patient-reported outcomes will be analysed by mixed effects regression models to estimate differences in mean scores between baseline and follow-ups whereas cost-effectiveness will be assessed using the incremental cost-effectiveness ratio. ETHICS AND DISSEMINATION:Ethics approval for this study was granted from the local Ethics Committees or Institutional Review Board from each of the participating sites prior to patient enrolment. The results of this study will be published in peer-reviewed journals and presented at different conferences. TRIAL REGISTRATION NUMBER:ClinicalTrials.gov: NCT02297581; pre-results.

Project description:This report provides an overview and a comparison of the burden and management of fragility fractures in the largest five countries of the European Union plus Sweden (EU6). In 2017, new fragility fractures in the EU6 are estimated at 2.7 million with an associated annual cost of €37.5 billion and a loss of 1.0 million quality-adjusted life years.Introduction: Osteoporosis is characterized by reduced bone mass and strength, which increases the risk of fragility fractures, which in turn, represent the main consequence of the disease. This report provides an overview and a comparison of the burden and management of fragility fractures in the largest five EU countries and Sweden (designated the EU6).Methods: A series of metrics describing the burden and management of fragility fractures were defined by a scientific steering committee. A working group performed the data collection and analysis. Data were collected from current literature, available retrospective data and public sources. Different methods were applied (e.g. standard statistics and health economic modelling), where appropriate, to perform the analysis for each metric.Results: Total fragility fractures in the EU6 are estimated to increase from 2.7 million in 2017 to 3.3 million in 2030; a 23% increase. The resulting annual fracture-related costs (€37.5 billion in 2017) are expected to increase by 27%. An estimated 1.0 million quality-adjusted life years (QALYs) were lost in 2017 due to fragility fractures. The current disability-adjusted life years (DALYs) per 1000 individuals age 50 years or more were estimated at 21 years, which is higher than the estimates for stroke or chronic obstructive pulmonary disease. The treatment gap (percentage of eligible individuals not receiving treatment with osteoporosis drugs) in the EU6 is estimated to be 73% for women and 63% for men; an increase of 17% since 2010. If all patients who fracture in the EU6 were enrolled into fracture liaison services, at least 19,000 fractures every year might be avoided.Conclusions: Fracture-related burden is expected to increase over the coming decades. Given the substantial treatment gap and proven cost-effectiveness of fracture prevention schemes such as fracture liaison services, urgent action is needed to ensure that all individuals at high risk of fragility fracture are appropriately assessed and treated.

Project description:UnlabelledWe investigated change in health-related quality of life due to fracture in Australian adults aged over 50 years. Fractures reduce quality of life with the loss sustained at least over 12 months. At a population level, the loss was equivalent to 65 days in full health per fracture.PurposeWe aimed to quantify the change in health-related quality of life (HRQoL) that occurred as a consequence of a fracture using the EQ-5D-3 L questionnaire.MethodsAdults aged ≥50 years with a low to moderate energy fracture were recruited from eight study centres across Australia. This prospective study included an 18-month follow-up of participants recruited within 2 weeks of a fracture (hip, wrist, humerus, vertebral and ankle). Information collected at baseline and 4, 12 and 18 months included characteristics of participants such as income level, education and prior fracture status. At 12 months post-fracture, the cumulative loss of quality of life was estimated using multivariate regression analysis to identify the predictors of HRQoL loss.ResultsMean HRQoL for all participants before fracture was 0.86, with wrist fracture having the highest pre-fracture HRQoL (0.90), while vertebral fracture had the lowest (0.80). HRQoL declined to 0.42 in the immediate post-fracture period. Only participants with a wrist, humerus or ankle fracture returned to their pre-fracture HRQoL after 18 months. An increased loss of HRQoL over 12 months was associated with HRQoL prior to the fracture, hospitalisation, education and fracture site. The multiple regression explained 30 % of the variation in the cumulative HRQoL loss at 12 months post-fracture for all fractures.ConclusionLow to moderate energy fractures reduce HRQoL, and this loss is sustained for at least 12 months or, in the case of hip and spine fractures, at least 18 months. At a population level, this represents an average loss of 65 days in full health per fragility fracture. This significant burden reinforces the need for cost-effective fracture prevention strategies.

Project description:BackgroundTibiotalocalcaneal (TTC) intramedullary nailing has been suggested as an alternative to open reduction and internal fixation (ORIF) for the primary treatment of unstable fragility ankle fractures with a poor soft tissue envelope. This study aims to investigate the clinical efficacy of TTC intramedullary nail fixation for the primary treatment of unstable ankle fractures in frail elderly patients with poor soft tissue condition, by assessing the number of postoperative complications and the patient-reported functional outcomes.MethodsA retrospective cohort study was performed including patients with an unstable ankle fracture treated between 2015 and 2019 with TTC stabilization using a retrograde intramedullary hindfoot nail that was inserted without joint preparation and allowing immediate weight-bearing postoperatively. The primary outcome was the total number of postoperative complications.ResultsA total of 10 patients were included out of 365 operatively treated ankle fractures. The mean age was 85.2 years (range 66-92) with a mean follow-up of 11.2 months (range 6-16). Fracture types included AO/OTA 44-B2 (n = 1), 44-B3 (n = 6), 44-C1 (n = 2) and 44-C3 (n = 1). Postoperative complications were observed in 4 patients (40%), including 3 nonunions, 2 implant related complications and 1 wound infection. No wound healing disorder or below-the-knee amputation was observed. Four patients (40%) deceased between post-operative 6 to 16 months due to medical conditions unrelated to surgery. The mean Foot and Ankle Outcome Score was 52.6 (range 44.2-73.8).ConclusionHindfoot nailingis a viable treatment option in selected high-risk patients with an advanced age, unstable ankle fractures with significant bone loss, poor soft tissue condition and/or severely impaired pre-injury mobility. In a frail geriatric population, hindfoot nailing may be a safe alternative fixation method with a low risk of wound complication or major amputation. However, unprepared joint may lead to symptomatic nonunion after TTC intramedullary nailing.

Dataset Information

Geriatric fragility fractures are associated with a human skeletal stem cell defect.

Publications

Geriatric fragility fractures are associated with a human skeletal stem cell defect.

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