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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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Importance: Limited knowledge about interactions among health disorders impedes optimal patient care. Because comorbidities are common among patients 50 years and older with fractures, these fractures provide a useful setting for studying interactions among disorders., Objective: To define multimorbidity clusters at the time of fracture and quantify the interaction between multimorbidity and fracture in association with postfracture excess mortality., Design, Setting, and Participants: This nationwide cohort study included 307 870 adults in Denmark born on or before January 1, 1951, who had an incident low-trauma fracture between January 1, 2001, and December 31, 2014, and were followed up through December 31, 2016. Data were analyzed from February 1 to March 31, 2022., Main Outcomes and Measures: Fracture and 32 predefined chronic diseases recorded within 5 years before the index fracture were identified from the Danish National Hospital Discharge Register. Death was ascertained from the Danish Register on Causes of Death. Latent class analysis was conducted to identify multimorbidity clusters. Relative survival analysis was used to quantify excess mortality associated with the combination of multimorbidity and fractures at specific sites., Results: Among the 307 870 participants identified with incident fractures, 95 372 were men (31.0%; mean [SD] age at fracture, 72.3 [11.2] years) and 212 498 were women (69.0%; mean [SD] age at fracture, 74.9 [11.2] years). During a median of 6.5 (IQR, 3.0-11.0) years of follow-up, 41 017 men (43.0%) and 81 727 women (38.5%) died. Almost half of patients with fractures (42.9%) had at least 2 comorbidities. Comorbidities at fracture were categorized as low-multimorbidity (60.5% in men and 66.5% in women), cardiovascular (23.7% in men and 23.5% in women), diabetic (5.6% in men and 5.0% in women), malignant (5.1% in men and 5.0% in women), and mixed hepatic and/or inflammatory (5.1% in men only) clusters. These clusters distinguished individuals with advanced, complex, or late-stage disease from those with earlier-stage disease. Multimorbidity and proximal or lower leg fractures were associated with increased mortality risk, with the highest excess mortality found in patients with hip fracture in the malignant cluster (1-year excess mortality: 40.8% [95% CI: 38.1%-43.6%]). The combination of multimorbidity and fracture compounded the association with mortality, conferring much greater risk than either alone., Conclusions and Relevance: Concomitant illnesses were common and clustered into distinct multimorbidity clusters that were associated with excess postfracture mortality. The compound contribution of multimorbidity to postfracture excess mortality highlights the need for more comprehensive approaches in these high-risk patients. The analytical approach applied to fracture could also be used to examine other sentinel health events.

Context: Little is known about long-term excess mortality following fragility nonhip fractures., Objective: The study aimed to determine which fracture was associated with excess mortality and for how long the postfracture excess mortality persisted., Design, Setting, and Patients: This nationwide registry-based follow-up study included all individuals in Denmark aged 50+ years who first experienced fragility fractures in 2001 and were followed up for up to 10 years for their mortality risk., Main Outcome Measure: The contribution of fracture to mortality at precise postfracture time intervals was examined using relative survival analysis, accounting for time-related mortality changes in the background population., Results: There were 21,123 women (aged 72 ± 13 years) and 9481 men (aged 67 ± 12 years) with an incident fragility fracture in 2001, followed by 10,668 and 4745 deaths, respectively. Excess mortality was observed following all proximal and lower leg fractures. The majority of deaths occurred within the first year after fracture, and thereafter excess mortality gradually declined. Hip fractures were associated with the highest excess mortality (33% and 20% at 1 year after fracture in men and women, respectively). One-year excess mortality after fracture of a femur or pelvis was 20% to 25%; vertebrae, 10%; humerus, rib, or clavicle, 5% to 10%; and lower leg, 3%. A significant although smaller excess mortality was still observed until 10 years for hip fractures and ~5 years after femur, other proximal, and lower leg fractures., Conclusion: This study highlights the important contribution of a wide variety of fragility fractures to long-term excess mortality and thus the potential for benefit from early intervention.

Low bone mineral density (BMD) is used as a parameter of osteoporosis. Genome-wide association studies of BMD have hitherto focused on BMD as a quantitative trait, yielding common variants of small effects that contribute to the population diversity in BMD. Here we use BMD as a dichotomous trait, searching for variants that may have a direct effect on the risk of pathologically low BMD rather than on the regulation of BMD in the healthy population. Through whole-genome sequencing of Icelandic individuals, we found a rare nonsense mutation within the leucine-rich-repeat-containing G-protein-coupled receptor 4 (LGR4) gene (c.376C>T) that is strongly associated with low BMD, and with osteoporotic fractures. This mutation leads to termination of LGR4 at position 126 and fully disrupts its function. The c.376C>T mutation is also associated with electrolyte imbalance, late onset of menarche and reduced testosterone levels, as well as an increased risk of squamous cell carcinoma of the skin and biliary tract cancer. Interestingly, the phenotype of carriers of the c.376C>T mutation overlaps that of Lgr4 mutant mice.

Background: Bone mineral density influences the risk of osteoporosis later in life and is useful in the evaluation of the risk of fracture. We aimed to identify sequence variants associated with bone mineral density and fracture., Methods: We performed a quantitative trait analysis of data from 5861 Icelandic subjects (the discovery set), testing for an association between 301,019 single-nucleotide polymorphisms (SNPs) and bone mineral density of the hip and lumbar spine. We then tested for an association between 74 SNPs (most of which were implicated in the discovery set) at 32 loci in replication sets of Icelandic, Danish, and Australian subjects (4165, 2269, and 1491 subjects, respectively)., Results: Sequence variants in five genomic regions were significantly associated with bone mineral density in the discovery set and were confirmed in the replication sets (combined P values, 1.2x10(-7) to 2.0x10(-21)). Three regions are close to or within genes previously shown to be important to the biologic characteristics of bone: the receptor activator of nuclear factor-kappaB ligand gene (RANKL) (chromosomal location, 13q14), the osteoprotegerin gene (OPG) (8q24), and the estrogen receptor 1 gene (ESR1) (6q25). The two other regions are close to the zinc finger and BTB domain containing 40 gene (ZBTB40) (1p36) and the major histocompatibility complex region (6p21). The 1p36, 8q24, and 6p21 loci were also associated with osteoporotic fractures, as were loci at 18q21, close to the receptor activator of the nuclear factor-kappaB gene (RANK), and loci at 2p16 and 11p11., Conclusions: We have discovered common sequence variants that are consistently associated with bone mineral density and with low-trauma fractures in three populations of European descent. Although these variants alone are not clinically useful in the prediction of risk to the individual person, they provide insight into the biochemical pathways underlying osteoporosis., (Copyright 2008 Massachusetts Medical Society.)