ABSTRACT
PURPOSE: To identify the optimal statistical approach for predicting the risk of fragility fractures in the presence of competing event of death. METHODS: We used real-world data from the Dubbo Osteoporosis Epidemiology Study that has monitored 3035 elderly participants for bone health and mortality. Fragility fractures were ascertained radiologically. Mortality was confirmed by the State Registry. We considered four statistical models for predicting fracture risk: (i) conventional Cox's proportional hazard model, (ii) cause-specific model, (iii) Fine-Gray sub-distribution model, and (iv) multistate model. These models were fitted and validated in the development (60% of the original sample) and validation (40%) subsets, respectively. The model performance was assessed by discrimination and calibration analyses. RESULTS: During a median follow-up of 11.3 years (IQR: 7.2, 16.2), 628 individuals (34.5%) in the development cohort fractured, and 630 (34.6%) died without a fracture. Neither the discrimination nor the 5-year prediction performance was significantly different among the models, though the conventional model tended to overestimate fracture risk (calibration-in-the-large index = - 0.24; 95% CI: - 0.43, - 0.06). For 10-year risk prediction, the multistate model (calibration-in-the-large index = - 0.05; 95% CI: - 0.20, 0.10) outperformed the cause-specific (- 0.23; - 0.30, - 0.08), Fine-Gray (- 0.31; - 0.46, - 0.16), and conventional model (- 0.54; - 0.70, - 0.39) which significantly overestimated fracture risk. CONCLUSION: Adjustment for competing risk of death has minimum impact on the short-term prediction of fracture. However, the multistate model yields the most accurate prediction of long-term fracture risk and should be considered for predictive research in the elderly, who are also at high mortality risk. Fracture risk assessment might be compromised by the competing event of death. This study, using real-world data found a multistate model was superior to the current competing risk methods in fracture risk assessment. A multistate model is considered an optimal statistical method for predictive research in the elderly.
ABSTRACT
A 55-year-old male with acute pericarditis presented with low-pressure cardiac tamponade (LPCT) unresponsive to volume infusion. Subsequent pericardiocentesis resulted in hemodynamic improvement and unmasking of pericardial constriction. This case provides illustrative hemodynamic tracings of LPCT. Additionally, the presence of concurrent pericardial constriction that may indicate a plausible underlying mechanism for the blunted responsiveness to fluid expansion in LPCT. The underlying physiologic processes and the associated hemodynamic tracings are discussed.
Subject(s)
Cardiac Tamponade , Hemodynamics , Pericardiocentesis , Humans , Cardiac Tamponade/physiopathology , Cardiac Tamponade/etiology , Cardiac Tamponade/diagnostic imaging , Cardiac Tamponade/surgery , Male , Middle Aged , Treatment Outcome , Pericarditis/physiopathology , Pericarditis/therapy , Pericarditis/diagnostic imaging , Pericarditis/etiology , Pericarditis/diagnosis , Acute DiseaseABSTRACT
RATIONALE: Comorbidities are common in fracture patients, but the interaction between fracture and comorbidities remains unclear. This study aimed to define specific multimorbidity clusters in older adults and quantify the association between the multimorbidity clusters and fracture risk. METHODS: This nationwide cohort study includes 1.7 million adults in Denmark aged ≥50 years who were followed from 2001 through 2014 for an incident low-trauma fracture. Chronic diseases and fractures were identified from the Danish National Hospital Discharge Register. Latent class analysis and Cox's regression were conducted to define the clusters and quantify fracture risk, respectively. RESULTS: The study included 793 815 men (age: 64 ± 10) and 873 524 women (65.5 ± 11), with a third having ≥1 chronic disease. The pre-existent chronic diseases grouped individuals into low-multimorbidity (80.3% in men, 83.6% in women), cardiovascular (12.5%, 10.6%), malignant (4.1%, 3.8%), diabetic (2.4%, 2.0%) and hepatic clusters (0.7%, men only). These clusters distinguished individuals with advanced, complex, or late-stage disease from those having earlier-stage disease. During a median follow-up of 14 years (IQR: 6.5, 14), 95 372 men and 212 498 women sustained an incident fracture. The presence of multimorbidity was associated with a significantly greater risk of fracture, independent of age and sex. Importantly, the multimorbidity clusters had the highest discriminative performance in assessing fracture risk, whereas the strength of their association with fracture risk equalled or exceeded that of both the individual chronic diseases most prevalent in each cluster and of counts-based comorbidity indices. CONCLUSIONS: Future fracture prevention strategies should take comorbidities into account. Multimorbidity clusters may provide greater insight into fracture risk than individual diseases or counts-based comorbidity indices.
Subject(s)
Fractures, Bone , Multimorbidity , Humans , Male , Female , Aged , Middle Aged , Denmark/epidemiology , Fractures, Bone/epidemiology , Risk Assessment , Risk Factors , Chronic Disease/epidemiology , Registries , Cluster Analysis , Incidence , Aged, 80 and overABSTRACT
Dual-energy X-ray absorptiometry (DXA) is the gold standard method for measuring bone mineral density (BMD) which is most strongly associated with fracture risk. BMD is therefore the basis for the World Health Organization's densitometric definition of osteoporosis. The International Society for Clinical Densitometry (ISCD) promotes best densitometry practices and its official positions reflect critical review of current evidence by domain experts. This document reports new official positions regarding follow-up DXA examinations based on a systematic review of literature published through December 2022. Adoption of official positions requires consensus agreement from an expert panel following a modified RAND protocol. Unless explicitly altered by the new position statements, prior ISCD official positions remain in force. This update reflects increased consideration of the clinical context prompting repeat examination. Follow-up DXA should be performed with pre-defined objectives when the results would have an impact on patient management. Testing intervals should be individualized according to the patient's age, sex, fracture risk and treatment history. Incident fractures and therapeutic approach are key considerations. Appropriately ordered and interpreted follow-up DXA examinations support diagnostic and therapeutic decision making, thereby contributing to excellent clinical care. Future research should address the complementary roles of clinical findings, imaging and laboratory testing to guide management.
Subject(s)
Fractures, Bone , Osteoporosis , Humans , Bone Density , Follow-Up Studies , Societies, Medical , Osteoporosis/diagnostic imaging , Absorptiometry, Photon , Fractures, Bone/diagnostic imagingABSTRACT
BACKGROUND: Multimorbidity is common among fracture patients. However, its association with osteoporosis investigation and treatment to prevent future fractures is unclear. This limited knowledge impedes optimal patient care. This study investigated the association between multimorbidity and osteoporosis investigation and treatment in persons at high risk following an osteoporotic fracture. METHODS AND FINDINGS: The Sax Institute's 45 and Up Study is a prospective population-based cohort of 267,153 people in New South Wales, Australia, recruited between 2005 and 2009. This analysis followed up participants until 2017 for a median of 6 years (IQR: 4 to 8). Questionnaire data were linked to hospital admissions (Admitted Patients Data Collection (APDC)), emergency presentations (Emergency Department Data Collection (EDDC)), Pharmaceutical Benefits Scheme (PBS), and Medicare Benefits Schedule (MBS). Data were linked by the Centre for Health Record Linkage and stored in a secured computing environment. Fractures were identified from APDC and EDDC, Charlson Comorbidity Index (CCI) from APDC, Dual-energy X-ray absorptiometry (DXA) investigation from MBS, and osteoporosis treatment from PBS. Out of 25,280 persons with index fracture, 10,540 were classified as high-risk based on 10-year Garvan Fracture Risk (age, sex, weight, prior fracture and falls) threshold ≥20%. The association of CCI with likelihood of investigation and treatment initiation was determined by logistic regression adjusted for education, socioeconomic and lifestyle factors). The high-risk females and males averaged 77 ± 10 and 86 ± 5 years, respectively; >40% had a CCI ≥2. Only 17% of females and 7% of males received a DXA referral, and 22% of females and 14% males received osteoporosis medication following fracture. A higher CCI was associated with a lower probability of being investigated [adjusted OR, females: 0.73 (95% CI, 0.61 to 0.87) and 0.43 (95% CI, 0.30 to 0.62); males: 0.47 (95% CI, 0.33 to 0.68) and 0.52 (0.31 to 0.85) for CCI: 2 to 3, and ≥4 versus 0 to 1, respectively] and of receiving osteoporosis medication [adjusted OR, females: 0.85 (95% CI, 0.74 to 0.98) and 0.78 (95% CI, 0.61 to 0.99); males: 0.75 (95% CI, 0.59 to 0.94) and 0.37 (95% CI, 0.23 to 0.53) for CCI: 2 to 3, and ≥4 versus 0 to 1, respectively]. The cohort is relatively healthy; therefore, the impact of multimorbidity on osteoporosis management may have been underestimated. CONCLUSIONS: Multimorbidity contributed significantly to osteoporosis treatment gap. This suggests that fracture risk is either underestimated or underprioritized in the context of multimorbidity and highlights the need for extra vigilance and improved fracture care in this setting.
Subject(s)
Osteoporosis , Osteoporotic Fractures , Male , Female , Humans , Aged , Prospective Studies , Multimorbidity , National Health Programs , Osteoporosis/complications , Osteoporosis/drug therapy , Osteoporosis/epidemiology , Osteoporotic Fractures/epidemiology , Osteoporotic Fractures/prevention & control , Australia/epidemiology , Absorptiometry, PhotonABSTRACT
The genetic causes of multiple congenital anomalies are incompletely understood. Here, we report novel heterozygous predicted loss-of-function (LoF) and predicted damaging missense variants in the WW domain binding protein 11 (WBP11) gene in seven unrelated families with a variety of overlapping congenital malformations, including cardiac, vertebral, tracheo-esophageal, renal and limb defects. WBP11 encodes a component of the spliceosome with the ability to activate pre-messenger RNA splicing. We generated a Wbp11 null allele in mouse using CRISPR-Cas9 targeting. Wbp11 homozygous null embryos die prior to E8.5, indicating that Wbp11 is essential for development. Fewer Wbp11 heterozygous null mice are found than expected due to embryonic and postnatal death. Importantly, Wbp11 heterozygous null mice are small and exhibit defects in axial skeleton, kidneys and esophagus, similar to the affected individuals, supporting the role of WBP11 haploinsufficiency in the development of congenital malformations in humans. LoF WBP11 variants should be considered as a possible cause of VACTERL association as well as isolated Klippel-Feil syndrome, renal agenesis or esophageal atresia.
Subject(s)
Abnormalities, Multiple/genetics , DNA-Binding Proteins/genetics , Haploinsufficiency/genetics , Kidney/metabolism , RNA Splicing Factors/genetics , Abnormalities, Multiple/pathology , Anal Canal/abnormalities , Anal Canal/pathology , Animals , Esophagus/abnormalities , Esophagus/metabolism , Esophagus/pathology , Heart Defects, Congenital/genetics , Heart Defects, Congenital/pathology , Heterozygote , Humans , Kidney/abnormalities , Kidney/pathology , Limb Deformities, Congenital/genetics , Limb Deformities, Congenital/pathology , Loss of Function Mutation/genetics , Mice , RNA Splicing/genetics , Spine/abnormalities , Spine/pathology , Trachea/abnormalities , Trachea/pathologyABSTRACT
PURPOSE OF REVIEW: To critically assess recent evidence concerning osteoporosis fracture risk. RECENT FINDINGS: Robust instruments exist for predicting factures incorporating well-documented risk factors especially prior fracture whose magnitude varies with site, occurrence time, and age. Stratifying time-since-prior fracture has resulted in the concept of imminent fracture risk and increased focus on secondary fracture prevention. Secondary fracture prevention recommendations include fracture liaison service, pharmacologic and non-pharmacologic multidisciplinary intervention, and communicating that fractures in older adults are the predictable consequence of underlying osteoporosis rather than unfortunate accidents. Quality improvement in osteoporosis care includes diagnosing osteoporosis on the basis of clinical fractures rather than exclusively relying on bone density testing; applying diagnostic rather than screening approaches to patients with prior fractures; regularly updating fall and fracture histories; performing a physical exam focused on spinal curvature, posture, and musculoskeletal function; reviewing images to identify prevalent fractures that may have been missed; and general use of fracture risk algorithms at all stages of osteoporosis management. Communicating effectively with patients about osteoporosis and fractures, their consequences, and pharmacological and non-pharmacological management is the cornerstone of high-value care.
Subject(s)
Osteoporotic Fractures/prevention & control , Risk Assessment/methods , Accidental Falls/prevention & control , Algorithms , Bone Density , Humans , Risk Factors , Secondary PreventionABSTRACT
Vertebral malformations (VMs) are caused by alterations in somitogenesis and may occur in association with other congenital anomalies. The genetic etiology of most VMs remains unknown and their identification may facilitate the development of novel therapeutic and prevention strategies. Exome sequencing was performed on both the discovery cohort of nine unrelated probands from the USA with VMs and the replication cohort from China (Deciphering Disorders Involving Scoliosis & COmorbidities study). The discovery cohort was analyzed using the PhenoDB analysis tool. Heterozygous and homozygous, rare and functional variants were selected and evaluated for their ClinVar, HGMD, OMIM, GWAS, mouse model phenotypes, and other annotations to identify the best candidates. Genes with candidate variants in three or more probands were selected. The replication cohort was analyzed by another in-house developed pipeline. We identified rare heterozygous variants in KIAA1217 in four out of nine probands in the discovery cohort and in five out of 35 probands in the replication cohort. Collectively, we identified 11 KIAA1217 rare variants in 10 probands, three of which have not been described in gnomAD and one of which is a nonsense variant. We propose that genetic variations of KIAA1217 may contribute to the etiology of VMs.
Subject(s)
Proteins/genetics , Spinal Diseases/genetics , Adolescent , Cervical Vertebrae/abnormalities , Child , Codon, Nonsense , Databases, Genetic , Female , Heterozygote , Homozygote , Humans , Male , Spinal Diseases/etiology , Thoracic Vertebrae/abnormalitiesABSTRACT
PURPOSE: To characterize clinically measurable endophenotypes, implicating the TBX6 compound inheritance model. METHODS: Patients with congenital scoliosis (CS) from China(N = 345, cohort 1), Japan (N = 142, cohort 2), and the United States (N = 10, cohort 3) were studied. Clinically measurable endophenotypes were compared according to the TBX6 genotypes. A mouse model for Tbx6 compound inheritance (N = 52) was investigated by micro computed tomography (micro-CT). A clinical diagnostic algorithm (TACScore) was developed to assist in clinical recognition of TBX6-associated CS (TACS). RESULTS: In cohort 1, TACS patients (N = 33) were significantly younger at onset than the remaining CS patients (P = 0.02), presented with one or more hemivertebrae/butterfly vertebrae (P = 4.9 × 10â8), and exhibited vertebral malformations involving the lower part of the spine (T8-S5, P = 4.4 × 10â3); observations were confirmed in two replication cohorts. Simple rib anomalies were prevalent in TACS patients (P = 3.1 × 10â7), while intraspinal anomalies were uncommon (P = 7.0 × 10â7). A clinically usable TACScore was developed with an area under the curve (AUC) of 0.9 (P = 1.6 × 10â15). A Tbx6-/mh (mild-hypomorphic) mouse model supported that a gene dosage effect underlies the TACS phenotype. CONCLUSION: TACS is a clinically distinguishable entity with consistent clinically measurable endophenotypes. The type and distribution of vertebral column abnormalities in TBX6/Tbx6 compound inheritance implicate subtle perturbations in gene dosage as a cause of spine developmental birth defects responsible for about 10% of CS.
Subject(s)
Gene Dosage , Inheritance Patterns , Scoliosis/congenital , Scoliosis/genetics , T-Box Domain Proteins/genetics , Animals , Cohort Studies , Disease Models, Animal , Humans , Mice , Models, Genetic , Scoliosis/classification , Scoliosis/pathology , Spine/pathologyABSTRACT
Inducible Cre-ERT recombinase technology is widely used for gene targeting studies. The second generation of inducible Cre-ERT recombinase, hemizygous B6.129S-Tg(UBC-cre/ERT2)1Ejb/J (hereafter abbreviated as Cre-ERT2), a fusion of a mutated estrogen receptor and Cre recombinase, was engineered to be more efficient and specific than the original Cre-ERT. The putative mechanism of selective Cre-mediated recombination is Cre sequestration in the cytoplasm in the basal state with translocation to the nucleus only in the presence of tamoxifen. We utilized both a reporter mouse (B6.129 (Cg)-Gt(ROSA)26Sor tm4(ACTB-tdTomato,-EGFP)Luo /J) and endothelin converting enzyme-1 floxed transgenic mouse line to evaluate Cre-ERT2 activity. We observed spontaneous Cre activity in both settings. Unintended Cre activity is a confounding factor that has a potentially large impact on data interpretation. Thus, it is important to consider background Cre activity in experimental design.
Subject(s)
Integrases/genetics , Integrases/metabolism , Mice, Transgenic , Transgenes , Animals , Endothelin-Converting Enzymes/genetics , Estrogen Receptor beta/genetics , Estrogen Receptor beta/metabolism , Mice, Inbred C57BL , Mice, Knockout , Tamoxifen/pharmacologyABSTRACT
Osteogenesis imperfecta (OI), or brittle bone disease, is most often caused by dominant mutations in the collagen I genes COL1A1/COL1A2, whereas rarer recessive OI is often caused by mutations in genes encoding collagen I-interacting proteins. Recently, mutations in the gene for the proteinase bone morphogenetic 1 (BMP1) were reported in two recessive OI families. BMP1 and the closely related proteinase mammalian tolloid-like 1 (mTLL1) are co-expressed in various tissues, including bone, and have overlapping activities that include biosynthetic processing of procollagen precursors into mature collagen monomers. However, early lethality of Bmp1- and Tll1-null mice has precluded use of such models for careful study of in vivo roles of their protein products. Here we employ novel mouse strains with floxed Bmp1 and Tll1 alleles to induce postnatal, simultaneous ablation of the two genes, thus avoiding barriers of Bmp1(-/-) and Tll1(-/-) lethality and issues of functional redundancy. Bones of the conditionally null mice are dramatically weakened and brittle, with spontaneous fractures-defining features of OI. Additional skeletal features include osteomalacia, thinned/porous cortical bone, reduced processing of procollagen and dentin matrix protein 1, remarkably high bone turnover and defective osteocyte maturation that is accompanied by decreased expression of the osteocyte marker and Wnt-signaling inhibitor sclerostin, and by marked induction of canonical Wnt signaling. The novel animal model presented here provides new opportunities for in-depth analyses of in vivo roles of BMP1-like proteinases in bone and other tissues, and for their roles, and for possible therapeutic interventions, in OI.
Subject(s)
Bone Morphogenetic Protein 1/genetics , Femur/pathology , Gene Knockdown Techniques/methods , Osteogenesis Imperfecta/pathology , Tolloid-Like Metalloproteinases/genetics , Animals , Bone Morphogenetic Protein 1/metabolism , Disease Models, Animal , Femur/ultrastructure , Humans , Mice , Mice, Inbred C57BL , Mutation , Osteogenesis Imperfecta/genetics , Tolloid-Like Metalloproteinases/metabolismABSTRACT
We report on a father and his two daughters diagnosed with Klippel-Feil syndrome (KFS) but with craniofacial differences (zygomatic and mandibular hypoplasia and cleft palate) and external ear abnormalities suggestive of Treacher Collins syndrome (TCS). The diagnosis of KFS was favored, given that the neck anomalies were the predominant manifestations, and that the diagnosis predated later recognition of the association between spinal segmentation abnormalities and TCS. Genetic heterogeneity and the rarity of large families with KFS have limited the ability to identify mutations by traditional methods. Whole exome sequencing identified a nonsynonymous mutation in POLR1D (subunit of RNA polymerase I and II): exon2:c.T332C:p.L111P. Mutations in POLR1D are present in about 5% of individuals diagnosed with TCS. We propose that this mutation is causal in this family, suggesting a pathogenetic link between KFS and TCS.
Subject(s)
Chromosome Segregation/genetics , DNA-Directed RNA Polymerases/genetics , Exome/genetics , Fathers , Klippel-Feil Syndrome/genetics , Mandibulofacial Dysostosis/genetics , Mutation/genetics , Nuclear Family , Child , Computational Biology , DNA Mutational Analysis , Family , Female , Genetic Association Studies , Humans , Infant, Newborn , Klippel-Feil Syndrome/complications , Male , Mandibulofacial Dysostosis/complications , PedigreeABSTRACT
PURPOSE OF REVIEW: The purpose is to discuss advances in the nutritional and pharmacological management of phenylketonuria (PKU). RECENT FINDINGS: Glycomacropeptide (GMP), a whey protein produced during cheese production, is a low-phenylalanine (phe) intact protein that represents a new dietary alternative to synthetic amino acids for people with PKU. Skeletal fragility is a long-term complication of PKU that based on murine research, appears to result from both genetic and nutritional factors. Skeletal fragility in murine PKU is attenuated with the GMP diet, compared with an amino acid diet, allowing greater radial bone growth. Pharmacologic therapy with tetrahydrobiopterin, acting as a molecular chaperone for phenylalanine hydroxylase, increases tolerance to dietary phe in some individuals. Large neutral amino acids inhibit phe transport across the intestinal mucosa and blood-brain barrier, and are most effective for individuals unable to comply with the low-phe diet. SUMMARY: Although a low-phe synthetic amino acid diet remains the mainstay of PKU management, new nutritional and pharmacological treatment options offer alternative approaches to maintain lifelong low phe concentrations. GMP medical foods provide an alternative to amino acid formula that may improve bone health, and tetrahydrobiopterin permits some individuals with PKU to increase tolerance to dietary phe. Further research is needed to characterize the long-term efficacy of these new approaches for PKU management.
Subject(s)
Phenylketonurias/diet therapy , Phenylketonurias/drug therapy , Amino Acids/administration & dosage , Biopterins/analogs & derivatives , Biopterins/pharmacology , Bone and Bones/drug effects , Bone and Bones/metabolism , Caseins/analysis , Caseins/pharmacology , Dietary Supplements , Humans , Milk Proteins/analysis , Milk Proteins/pharmacology , Mutation , Peptide Fragments/analysis , Peptide Fragments/pharmacology , Phenylalanine/administration & dosage , Phenylalanine/blood , Phenylalanine Hydroxylase/genetics , Phenylalanine Hydroxylase/metabolism , Phenylketonurias/blood , Randomized Controlled Trials as Topic , Tyrosine/metabolism , Whey ProteinsABSTRACT
INTRODUCTION: Endothelin (ET1) promotes the growth of osteoblastic breast and prostate cancer metastases. Conversion of big ET1 to mature ET1, catalyzed primarily by endothelin converting enzyme 1 (ECE1), is necessary for ET1's biological activity. We previously identified the Ece1, locus as a positional candidate gene for a pleiotropic quantitative trait locus affecting femoral size, shape, mineralization, and biomechanical performance. METHODS: We exposed TMOb osteoblasts continuously to 25 ng/ml big ET1. Cells were grown for 6 days in growth medium and then switched to mineralization medium for an additional 15 days with or without big ET1, by which time the TMOb cells form mineralized nodules. We quantified mineralization by alizarin red staining and analyzed levels of miRNAs known to affect osteogenesis. Micro RNA 126-3p was identified by search as a potential regulator of sclerostin (SOST) translation. RESULTS: TMOb cells exposed to big ET1 showed greater mineralization than control cells. Big ET1 repressed miRNAs targeting transcripts of osteogenic proteins. Big ET1 increased expression of miRNAs that target transcripts of proteins that inhibit osteogenesis. Big ET1 increased expression of 126-3p 121-fold versus control. To begin to assess the effect of big ET1 on SOST production we analyzed both SOST transcription and protein production with and without the presence of big ET1 demonstrating that transcription and translation were uncoupled. CONCLUSION: Our data show that big ET1 signaling promotes mineralization. Moreover, the results suggest that big ET1's osteogenic effects are potentially mediated through changes in miRNA expression, a previously unrecognized big ET1 osteogenic mechanism.
Subject(s)
Calcification, Physiologic/physiology , Cell Differentiation/physiology , Endothelin-1/metabolism , MicroRNAs/genetics , Osteoblasts/metabolism , Osteogenesis/physiology , Bone Morphogenetic Proteins/metabolism , Cells, Cultured , Humans , Signal Transduction/physiologyABSTRACT
Bone and muscle mass are highly correlated. In part, this is a consequence of both tissues sharing common genetic determinants. In addition, both tissues are responsive to their mechanical environments. New genetic tools in mice will allow genes of interest to be inactivated in experimentally defined contexts, thus allowing investigators to distinguish direct effects on each tissue from physiological responses to a primary phenotype in the other.
ABSTRACT
Importance: A high proportion of patients who sustain a fracture have multimorbidity. However, the association of multimorbidity with postfracture adverse outcomes, such as subsequent fractures and premature mortality, has not been widely explored. Objective: To examine the association of multimorbidity and self-rated health with subsequent fractures and mortality after fracture. Design, Setting, and Participants: This prospective cohort study included participants from New South Wales, Australia, in the Sax Institute's 45 and Up Study (n = 267â¯357). Participants were recruited from July 2005 to December 2009 and followed up from the date of the incident fracture until subsequent fracture, death, or the end of the study (April 2017), whichever occurred first, with questionnaire data linked to hospital admission and medication records. Data analysis was reported between March and September 2023. Exposures: Charlson Comorbidity Index (CCI) score and self-rated health (SRH). Main Outcomes and Measures: The main outcomes were subsequent fracture or mortality after an incident fracture. Associations between SRH measures and subsequent fracture and mortality were also assessed. All analyses were stratified by sex given the different fracture and mortality risk profiles of females and males. Results: Of 25â¯280 adults who sustained incident fractures, 16â¯191 (64%) were female (mean [SD] age, 74 [12] years) and 9089 (36%) were male (mean [SD] age, 74 [13] years). During a median follow-up time of 2.8 years (IQR, 1.1-5.2 years), 2540 females (16%) and 1135 males (12%) sustained a subsequent fracture and 2281 females (14%) and 2140 males (24%) died without a subsequent fracture. Compared with a CCI score of less than 2, those with a CCI score of 2 to 3 had an increased risk of subsequent fracture (females: hazard ratio [HR], 1.16 [95% CI, 1.05-1.27]; males: HR, 1.25 [95% CI, 1.09-1.43]) and mortality (females: HR, 2.19 [95% CI, 1.99-2.40]; males: HR, 1.89 [95% CI, 1.71-2.09]). Those with a CCI score of 4 or greater had greater risks of subsequent fracture (females: HR, 1.33 [95% CI, 1.12-1.58]; males: HR, 1.48 [95% CI, 1.21-1.81]) and mortality (females: HR, 4.48 [95% CI, 3.97-5.06]; males: HR, 3.82 [95% CI 3.41-4.29]). Self-rated health was also significantly associated with subsequent fracture and mortality. Those reporting the poorest health and quality of life had the highest subsequent fracture risks, and their mortality risks were even higher. Conclusions and Relevance: In this cohort study, both CCI and SRH measures were associated with increased risk of subsequent fractures and mortality after fracture, underscoring the importance of managing the care of patients with comorbidities who sustain a fracture.
Subject(s)
Fractures, Bone , Multimorbidity , Humans , Male , Female , Aged , Prospective Studies , Fractures, Bone/epidemiology , Fractures, Bone/mortality , New South Wales/epidemiology , Middle Aged , Aged, 80 and overABSTRACT
Importance: The relationship between self-reported walking limitation, a proxy of muscle function, and fracture risk has not been investigated. Objective: To examine the association between a self-reported walking limitation of 1000 m or less and 5-year risk of fracture. Design, Setting, and Participants: This prospective cohort study compared individuals with various degrees of walking ability limitation at 1000 m (a little limitation and a lot of limitation) and those without limitation (no limitation) accounting for age, falls, prior fractures, and weight. Participants from the ongoing population-based Sax Institute 45 and Up Study were followed from recruitment (2005-2008) for 5 years (2010-2013). Data analysis was conducted from July 2020 to September 2023. Exposure: Self-reported walking limitation. Main Outcomes and Measures: Incident fracture and site-specific fractures (hip, vertebral, and nonhip nonvertebral [NHNV] fractures). Results: Among the 266â¯912 participants enrolled in the 45 and Up Study, 238â¯969 were included, with 126â¯015 (53%) women (mean [SD] age, 63 [11] years) and 112â¯954 (47%) men (mean [SD] age, 61 [11] years). Approximately 20% reported a degree of limitation in walking 1000 m or less at baseline (39â¯324 women [24%]; 23â¯191 men [21%]). During a mean (SD) follow-up of 4.1 (0.8) years, 7190 women and 4267 men experienced an incident fracture. Compared with participants who reported no walking limitations, a little limitation and a lot of limitation were associated with higher risk of fracture (a little limitation among women: hazard ratio [HR], 1.32; 95% CI, 1.23-1.41; a little limitation among men: HR, 1.46; 95% CI, 1.34-1.60; a lot of limitation among women: HR, 1.60; 95% CI, 1.49-1.71; a lot of limitation among men: HR, 2.03; 95% CI, 1.86-2.22). Approximately 60% of fractures were attributable to walking limitation. The association was significant for hip, vertebral, and NHNV fracture and ranged between a 21% increase to a greater than 219% increase. Conclusions and Relevance: In this cohort study of 238â¯969 participants, self-reported walking limitations were associated with increased risk of fracture. These findings suggest that walking ability should be sought by clinicians to identify high-risk candidates for further assessment.
Subject(s)
Fractures, Bone , Self-Assessment , Adult , Male , Humans , Female , Aged , Middle Aged , Australia/epidemiology , Cohort Studies , Prospective Studies , Academies and Institutes , Fractures, Bone/epidemiologyABSTRACT
A survey of awareness and attitudes to the management of fragility fractures among the membership of the Asia Pacific Orthopaedic Association conducted in 2022 found considerable variation in care across the region. A Call to Action is proposed to improve acute care, rehabilitation and secondary fracture prevention across Asia Pacific. PURPOSE: Fragility fractures impose a substantial burden on older people and their families, healthcare systems and national economies. The current incidence of hip and other fragility fractures across the Asia Pacific region is enormous and set to escalate rapidly in the coming decades. This publication describes findings of a survey of awareness and attitudes to the management of fragility fractures among the membership of the Asia Pacific Orthopaedic Association (APOA) conducted in 2022. METHODS: The survey was developed as a collaboration between the Asia Pacific Osteoporosis and Fragility Fracture Society and the Asia Pacific Fragility Fracture Alliance, and included questions relating to aspects of care upon presentation, during surgery and mobilisation, secondary fracture prevention, and access to specific services. RESULTS: In total, 521 APOA members completed the survey and marked variation in delivery of care was evident. Notable findings included: Fifty-nine percent of respondents indicated that analgesia was routinely initiated in transit (by paramedics) or within 30 minutes of arrival in the Emergency Department. One-quarter of respondents stated that more than 80% of their patients underwent surgery within 48 hours of admission. One-third of respondents considered non-hip, non-vertebral fractures to merit assessment of future fracture risk. One-third of respondents reported the presence of an Orthogeriatric Service in their hospital, and less than a quarter reported the presence of a Fracture Liaison Service. CONCLUSION: A Call to Action for all National Orthopaedic Associations affiliated with APOA is proposed to improve the care of fragility fracture patients across the region.