Higher serum free thyroxine levels are associated with increased risk of hip fractures in older men.

Overt and subclinical hyperthyroidism are associated with an increased fracture risk, but whether thyroid hormones are associated with fracture risk in individuals with normal thyroid-stimulating hormone (TSH) has mostly been investigated in women. Therefore, we investigated if serum levels of free thyroxine (FT4) or TSH are associated with fracture risk in Swedish men. We followed (median 12.2 yr) elderly men (n = 1825; mean age 75, range 69-81 yr) participating in the Gothenburg and Malmö subcohorts of the prospective, population-based MrOS-Sweden study. The statistical analyses included Cox proportional hazards regression. Men receiving levothyroxine treatment were excluded. In our total cohort, serum FT4 (per SD increase) was associated with increased risk of major osteoporotic fractures (MOFs; n = 479; fully adjusted hazard ratio [HR] 1.14, 95% CI, 1.05-1.24) and hip fractures (n = 207; HR 1.18, 95% CI, 1.04-1.33). Also, in men with normal TSH (n = 1658), FT4 (per SD increase) was significantly associated with increased risk of MOF and hip fractures. Furthermore, men in the highest FT4 quartile had a 1.5-fold increase in hip fracture risk compared with men in the three lower FT4 quartiles, both in the total population and in men with normal TSH (fully adjusted: HR 1.45, 95% CI, 1.04-2.02 and HR 1.51, 95% CI, 1.07-2.12, respectively). In contrast, the risk of MOF was not statistically different in the highest FT4 quartile compared with the three lower FT4 quartiles. Finally, serum TSH was not associated with fracture risk after full adjustment for covariates. In conclusion, serum FT4, but not serum TSH, is a predictor of hip fracture risk in elderly Swedish men. Additionally, there was an association between FT4 (per SD increase) and the risk of MOF.

Sarcopenia definitions and their association with fracture risk in older Swedish women.

The purpose of this study was to investigate the prevalence of three sarcopenia definitions and their associations with fracture risk in older Swedish women when adjusted for fracture risk assessment (FRAX)-based risk factors; 2,883 women with a mean age of 77.8 years were included. Sarcopenia was defined based on the Sarcopenia Definitions and Outcomes Consortium (SDOC; low handgrip strength [kg] and gait speed (m/s)), revised European Working Group on Sarcopenia in Older People (EWGSOP2; low appendicular lean mass index, appendicular lean mass [ALM]/height; kg/m2], and hand grip strength [kg]), and Asian Working Group for Sarcopenia (AWGS; low ALM (kg), and hand grip strength [kg]) definitions. Femoral neck T-score was obtained from dual-energy X-ray absorptiometry. All fractures, confirmed by X-ray or medical record review, were subsequently categorized as major osteoporotic fractures (MOFs) and hip fractures. Deaths were verified through regional registers. The total follow-up time was 6.4 ± 1.3 (mean ± SD) yr. Cox regression (hazard ratios [HR] and 95% CIs) analyses were performed with adjustment for age, FRAX variables, and femoral neck T-score. Sarcopenia prevalence was 4.5% (n = 129) according to SDOC, 12.5% (n = 360) for EWGSOP2, and 10.3% (n = 296) defined by AWGS. Individuals with sarcopenia defined by SDOC had a higher mortality risk than individuals without sarcopenia (HR: 3.41; 95% CI: 2.51, 4.62) after adjusting for age and FRAX variables. Sarcopenia according to EWGSOP2 and AWGS was not associated with an increased fracture risk after adjusting for age and FRAX variables. Individuals with sarcopenia defined by SDOC had a higher risk for any fractures (HR: 1.48; 95% CI: 1.10, 1.99) and MOF (HR: 1.42; 95% CI: 1.03, 1.98) compared with individuals without sarcopenia after adjusting for clinical risk factors used in FRAX. In conclusion, sarcopenia defined by SDOC, incorporating muscle function/strength, was the only sarcopenia definition associated with fracture risk in older women.

This study aimed to investigate the risk of sarcopenia on fracture risk in older Swedish women. Data were utilized from 2,883 women aged 75­80 yr in the Swedish Sahlgrenska University Hospital Prospective Evaluation of Risk of Bone Fractures cohort. Sarcopenia was defined using three different definitions, including the Sarcopenia Definitions and Outcomes Consortium (SDOC), which includes grip strength and gait speed, while the revised European Working Group on Sarcopenia in Older People (EWGSOP2) and the Asian Working Group for Sarcopenia (AWGS) definitions include appendicular lean mass measured by dual-energy X-ray absorptiometry and grip strength. The results demonstrated that SDOC-defined sarcopenia was associated with a higher mortality risk, with increased risk of any fractures, and major osteoporotic fractures, whereas the EWGSOP2 and AWGS definitions were not associated with fracture risk. In summary, the study demonstrates that sarcopenia defined by SDOC, considering muscle function and strength, rather than lean mass, was the only investigated sarcopenia definition associated with fracture risk.

The significance of recent fracture location for imminent risk of hip and vertebral fractures-a nationwide cohort study on older adults in Sweden.

The role of recent fracture site in predicting the most detrimental subsequent fractures, hip and vertebral, is unclear. This study found that most recent fracture sites were associated with an increased risk of both hip and vertebral fracture, a finding that may impact the design of secondary prevention programs. BACKGROUND: Hip and vertebral fractures are the most serious in terms of associated morbidity, mortality, and societal costs. There is limited evidence as to which fracture types are associated with the highest risk for subsequent hip and vertebral fractures. This study aims to explore the dependency of imminent hip and vertebral fracture risk on the site of the recent index fracture. METHODS: Conducted as a nationwide retrospective cohort study, we utilized Swedish national registers to assess the risk of hip and vertebral fractures based on the site of the recent (≤ 2 years) index fracture and an old (> 2 years) prevalent fracture. This risk was compared to that observed in individuals without any prevalent fractures. This study encompassed all Swedes aged 50 years and older between 2007 and 2010. Patients with a recent fracture were categorized into specific groups based on the type of their previous fracture and were followed until December 2017, with censoring for death and migration. The study assessed the risk of hip and vertebral fractures during the follow-up period. RESULTS: The study included a total of 3,423,320 individuals, comprising 145,780 with a recent fracture, 293,051 with an old fracture, and 2,984,489 without a previous fracture. The median follow-up times for the three groups were 7.6 years (IQR 4.0-9.1), 7.9 years (5.8-9.2), and 8.5 years (7.4-9.7), respectively. Patients with a recent fracture at almost all sites exhibited a significantly increased risk of hip fracture and an elevated risk of vertebral fracture compared to controls. Patients with recent fractures had an increased risk of subsequent hip and vertebral fractures, regardless of the index fracture site. These results strengthen the notion that all patients with a recent fracture, regardless of fracture site, should be included in secondary prevention programs, to improve the prevention of the clinically most serious fractures.

Adjusting FRAX Estimates of Fracture Probability Based on a Positive Vertebral Fracture Assessment.

Importance: FRAX is the most widely used and validated fracture risk prediction tool worldwide. Vertebral fractures, which are an indicator of subsequent osteoporotic fractures, can be identified using dual-energy x-ray absorptiometry (DXA) vertebral fracture assessment (VFA). Objective: To assess the calibration of FRAX and develop a simple method for improving FRAX-predicted fracture probability in the presence of VFA-identified fracture. Design, Setting, and Participants: This prognostic study analyzed the DXA and VFA results of all individuals who underwent a VFA between March 31, 2010, and March 31, 2018, who were included in the Manitoba Bone Mineral Density Registry. These individuals were randomly assigned to either the development cohort or validation cohort. A modified algorithm-based qualitative approach was used by expert readers to code VFAs as positive (≥1 vertebral fractures detected) or negative (0 vertebral fracture detected). Statistical analysis was conducted from August 7, 2022, to May 22, 2023. Exposures: FRAX scores for major osteoporotic fracture (MOF) and hip fracture were calculated with or without VFA results. Main Outcomes and Measures: Incident fractures and death were ascertained using linked population-based health care provincial data. Cumulative incidence curves for MOF and hip fracture were constructed, including competing mortality, to predict the 10-year observed risk of fracture. The observed probability was compared with FRAX-predicted fracture probability with and without VFA results and recalibrated FRAX from derived multipliers. Results: The full cohort of 11 766 individuals was randomly allocated to the development cohort (n = 7854; 7349 females [93.6%]; mean [SD] age, 75.7 [6.8] years) or the validation cohort (n = 3912; 3713 females [94.9%]; mean [SD] age, 75.5 [6.9] years). Over a mean (SD) observation time of 3.8 (2.3) years, with the longest observation at 7.5 years, FRAX was well calibrated in subgroups with negative VFA results. For individuals without a prior clinical fracture but with a positive VFA result, the 10-year FRAX-predicted MOF probability was 16.3% (95% CI, 15.7%-16.8%) without VFA information and 23.4% (95% CI, 22.7%-24.1%) with VFA information. The observed 10-year probabilities were 26.9% (95% CI, 26.0%-27.8%) and 11.2% (95% CI, 10.3%-12.1%), respectively, resulting in recalibration multipliers of 1.15 (95% CI, 0.87-1.43) for MOF and 1.31 (95% CI, 0.75-1.87) for hip fracture. For individuals with a prior clinical fracture and a positive VFA result, the 10-year FRAX-predicted probabilities were 25.0% (95% CI, 24.2%-25.7%) for MOF and 9.3% (95% CI, 8.7%-10.0%) for hip fracture. The observed 10-year probabilities were 38.1% (95% CI, 37.0%-39.1%) for MOF and 16.4% (95% CI, 15.4%-17.4%) for hip fracture, resulting in a recalibration multiplier of 1.53 (95% CI, 1.10-1.96) for MOF and 1.76 (95% CI, 1.17-2.35) for hip fracture. Good calibration (>0.90) was confirmed using the derived multipliers in the validation cohort. Conclusions and Relevance: Results of this prognostic study suggest that FRAX underestimated fracture risk in patients with VFA-identified fractures. Simple multipliers could recover FRAX calibration in individuals with VFA-identified fractures.

Synergy and oxygen adaptation for development of next-generation probiotics.

The human gut microbiota has gained interest as an environmental factor that may contribute to health or disease1. The development of next-generation probiotics is a promising strategy to modulate the gut microbiota and improve human health; however, several key candidate next-generation probiotics are strictly anaerobic2 and may require synergy with other bacteria for optimal growth. Faecalibacterium prausnitzii is a highly prevalent and abundant human gut bacterium associated with human health, but it has not yet been developed into probiotic formulations2. Here we describe the co-isolation of F. prausnitzii and Desulfovibrio piger, a sulfate-reducing bacterium, and their cross-feeding for growth and butyrate production. To produce a next-generation probiotic formulation, we adapted F. prausnitzii to tolerate oxygen exposure, and, in proof-of-concept studies, we demonstrate that the symbiotic product is tolerated by mice and humans (ClinicalTrials.gov identifier: NCT03728868 ) and is detected in the human gut in a subset of study participants. Our study describes a technology for the production of next-generation probiotics based on the adaptation of strictly anaerobic bacteria to tolerate oxygen exposures without a reduction in potential beneficial properties. Our technology may be used for the development of other strictly anaerobic strains as next-generation probiotics.

Hemoglobin Levels Improve Fracture Risk Prediction in Addition to FRAX Clinical Risk Factors and Bone Mineral Density.

CONTEXT: Anemia and decreasing levels of hemoglobin (Hb) have previously been linked to increased fracture risk, but the added value to FRAX, the most utilized fracture prediction tool worldwide, is unknown. OBJECTIVE: To investigate the association between anemia, Hb levels, bone microstructure, and risk of incident fracture and to evaluate whether Hb levels improve fracture risk prediction in addition to FRAX clinical risk factors (CRFs). METHODS: A total of 2778 community-dwelling women, aged 75-80 years, and part of a prospective population-based cohort study in Sweden were included. At baseline, information on anthropometrics, CRFs, and falls was gathered, blood samples were collected, and skeletal characteristics were investigated using dual-energy x-ray absorptiometry and high-resolution peripheral quantitative computed tomography. At the end of follow-up, incident fractures were retrieved from a regional x-ray archive. RESULTS: The median follow-up time was 6.4 years. Low Hb was associated with worse total hip and femoral neck bone mineral density (BMD), and lower tibia cortical and total volumetric BMD, and anemia was associated with increased risk of major osteoporotic fracture (MOF; hazard ratio 2.04; 95% CI 1.58-2.64). Similar results were obtained for hip fracture and any fracture, also when adjusting for CRFs. The ratio between 10-year fracture probabilities of MOF assessed in models with Hb levels included and not included ranged from 1.2 to 0.7 at the 10th and 90th percentile of Hb, respectively. CONCLUSION: Anemia and decreasing levels of Hb are associated with lower cortical BMD and incident fracture in older women. Considering Hb levels may improve the clinical evaluation of patients with osteoporosis and the assessment of fracture risk.

Bone mineral density loci specific to the skull portray potential pleiotropic effects on craniosynostosis.

Skull bone mineral density (SK-BMD) provides a suitable trait for the discovery of key genes in bone biology, particularly to intramembranous ossification, not captured at other skeletal sites. We perform a genome-wide association meta-analysis (n ~ 43,800) of SK-BMD, identifying 59 loci, collectively explaining 12.5% of the trait variance. Association signals cluster within gene-sets involved in skeletal development and osteoporosis. Among the four novel loci (ZIC1, PRKAR1A, AZIN1/ATP6V1C1, GLRX3), there are factors implicated in intramembranous ossification and as we show, inherent to craniosynostosis processes. Functional follow-up in zebrafish confirms the importance of ZIC1 on cranial suture patterning. Likewise, we observe abnormal cranial bone initiation that culminates in ectopic sutures and reduced BMD in mosaic atp6v1c1 knockouts. Mosaic prkar1a knockouts present asymmetric bone growth and, conversely, elevated BMD. In light of this evidence linking SK-BMD loci to craniofacial abnormalities, our study provides new insight into the pathophysiology, diagnosis and treatment of skeletal diseases.

FRAX Adjustment by Trabecular Bone Score with or Without Bone Mineral Density: The Manitoba BMD Registry.

Trabecular bone score (TBS), a texture measure derived from spine dual-energy x-ray absorptiometry (DXA) images, is a FRAX®-independent risk factor for fracture. The TBS adjustment to FRAX assumes the presence of femoral neck BMD in the calculation. However, there are many individuals in whom hip DXA cannot be acquired. Whether the TBS-adjustment would apply to FRAX probabilities calculated without BMD has not been studied. The current analysis was performed to evaluate major osteoporotic fracture (MOF) and hip fracture risk adjusted for FRAX with and without femoral neck BMD. The study cohort consisted of 71,209 individuals (89.8% female, mean age 64.0 years). During mean follow-up 8.7 years, 6743 (9.5%) individuals sustained one or more incident MOF, of which 2037 (2.9%) sustained a hip fracture. Lower TBS was significantly associated with increased fracture risk when adjusted for FRAX probabilities, with a slightly larger effect when BMD was not included. Inclusion of TBS in the risk calculation gave a small but significant increase in stratification for fracture probabilities estimated with and without BMD. Calibration plots showed very minor deviations from the line of identity, indicating overall good calibration. In conclusion, the existing equations for incorporating TBS in FRAX estimates of fracture probability work similarly when femoral neck BMD is not used in the calculation. This potentially extends the range of situations where TBS can be used clinically to those individuals in whom lumbar spine TBS is available but femoral neck BMD is not available.

Low Circulating Valine Associate With High Risk of Hip Fractures.

CONTEXT: Hip fractures constitute a major health concern. An adequate supply of amino acids is crucial to ensure optimal acquisition and remodeling of bone. Circulating amino acid levels have been proposed as markers of bone mineral density, but data on their ability to predict incident fractures are scarce. OBJECTIVES: To investigate the associations between circulating amino acids and incident fractures. METHODS: We used UK Biobank (n = 111 257; 901 hip fracture cases) as a discovery cohort and the Umeå Fracture and Osteoporosis (UFO) hip fracture study (hip fracture cases n = 2225; controls n = 2225) for replication. Associations with bone microstructure parameters were tested in a subsample of Osteoporotic Fractures in Men Sweden (n = 449). RESULTS: Circulating valine was robustly associated with hip fractures in the UK Biobank (HR per SD increase 0.79, 95% CI 0.73-0.84), and this finding was replicated in the UFO study (combined meta-analysis including 3126 incident hip fracture cases, odds ratio per SD increase 0.84, 95% CI 0.80-0.88). Detailed bone microstructure analyses showed that high circulating valine was associated with high cortical bone area and trabecular thickness. CONCLUSION: Low circulating valine is a robust predictor of incident hip fractures. We propose that circulating valine may add information for hip fracture prediction. Future studies are warranted to determine whether low valine is causally associated with hip fractures.

Increased Bone Material Strength Index Is Positively Associated With the Risk of Incident Osteoporotic Fractures in Older Swedish Women.

No previous studies have investigated the association between the bone material strength index (BMSi; an indicator of bone material properties obtained by microindentation) and the risk of incident fracture. The primary purpose of this prospective cohort study was to evaluate if BMSi is associated with incident osteoporotic fracture in older women and, secondarily, with prevalent fractures, anthropometric traits, or measurements of bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA). In a population-based cohort, 647 women aged 75 to 80 years underwent bone microindentation using the OsteoProbe device. Data on clinical risk factors (CRFs), prevalent fractures, and incident fractures were collected using questionnaires, medical records, and a regional X-ray archive. BMD and vertebral fracture assessment (VFA) were assessed by DXA (Hologic, Discovery A). Associations between BMSi, anthropometrics, BMD, and prevalent fractures were investigated using correlation and linear and logistic regression. Cox proportional hazards and competing risks analysis by Fine and Gray were used to study the association between BMSi and the risk of fracture and mortality. BMSi was weakly associated with age (r = -0.13, p < 0.001) and BMI (r = -0.21, p < 0.001) and with BMD of lumbar spine (ß = 0.09, p = 0.02) and total hip (ß = 0.08, p = 0.05), but only after adjustments. No significant associations were found between BMSi and prevalent fractures (self-reported and/or VFA identified, n = 332). During a median follow-up time of 6.0 years, 121 major osteoporotic fractures (MOF), 151 any fractures, and 50 deaths occurred. Increasing BMSi (per SD) was associated with increased risk of MOF (hazard ratio [HR] = 1.29, 95% confidence interval [CI] 1.07-1.56), any fracture (HR = 1.29, 95% CI 1.09-1.53), and mortality (HR = 1.44, 95% CI 1.07-1.93). The risk of fracture did not materially change with adjustment for confounders, CRFs, femoral neck BMD, or when considering the competing risk of death. In conclusion, unexpectedly increasing BMSi was associated with greater fracture risk. The clinical relevance and potential mechanisms of this finding require further study. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Lowering of Circulating Sclerostin May Increase Risk of Atherosclerosis and Its Risk Factors: Evidence From a Genome-Wide Association Meta-Analysis Followed by Mendelian Randomization.

OBJECTIVE: In this study, we aimed to establish the causal effects of lowering sclerostin, target of the antiosteoporosis drug romosozumab, on atherosclerosis and its risk factors. METHODS: A genome-wide association study meta-analysis was performed of circulating sclerostin levels in 33,961 European individuals. Mendelian randomization (MR) was used to predict the causal effects of sclerostin lowering on 15 atherosclerosis-related diseases and risk factors. RESULTS: We found that 18 conditionally independent variants were associated with circulating sclerostin. Of these, 1 cis signal in SOST and 3 trans signals in B4GALNT3, RIN3, and SERPINA1 regions showed directionally opposite signals for sclerostin levels and estimated bone mineral density. Variants with these 4 regions were selected as genetic instruments. MR using 5 correlated cis-SNPs suggested that lower sclerostin increased the risk of type 2 diabetes mellitus (DM) (odds ratio [OR] 1.32 [95% confidence interval (95% CI) 1.03-1.69]) and myocardial infarction (MI) (OR 1.35 [95% CI 1.01-1.79]); sclerostin lowering was also suggested to increase the extent of coronary artery calcification (CAC) (ß = 0.24 [95% CI 0.02-0.45]). MR using both cis and trans instruments suggested that lower sclerostin increased hypertension risk (OR 1.09 [95% CI 1.04-1.15]), but otherwise had attenuated effects. CONCLUSION: This study provides genetic evidence to suggest that lower levels of sclerostin may increase the risk of hypertension, type 2 DM, MI, and the extent of CAC. Taken together, these findings underscore the requirement for strategies to mitigate potential adverse effects of romosozumab treatment on atherosclerosis and its related risk factors.

The Importance of Recent Prevalent Fracture Site for Imminent Risk of Fracture - A Retrospective, Nationwide Cohort Study of Older Swedish Men and Women.

There is limited evidence regarding which fracture types carry the highest risk for subsequent fracture. The aim of this study was to investigate how the risk of imminent fracture depends on index fracture site. This nationwide retrospective cohort study utilized national registers in Sweden to determine the risk of fracture according to recent (≤2 years) index fracture site and according to an old (>2 years) prevalent fracture compared with the risk observed in controls without a fracture. All Swedes 50 years or older between 2007 and 2010 were included in the study. Patients with a recent fracture were designated a specific fracture group depending on the type of previous fracture. Recent fractures were classified as major osteoporotic fracture (MOF), including fractured hip, vertebra, proximal humerus, and wrist, or non-MOF. Patients were followed until December 31, 2017, censored for death and emigration, and the risk of any fracture and hip fracture was assessed. A total of 3,423,320 persons were included in the study, 70,254 with a recent MOF, 75,526 with a recent non-MOF, 293,051 with an old fracture, and 2,984,489 persons with no previous fracture. The median time of follow-up for the four groups was 6.1 (interquartile range [IQR] 3.0-8.8), 7.2 (5.6-9.4), 7.1 (5.8-9.2), and 8.1 years (7.4-9.7), respectively. Patients with a recent MOF, recent non-MOF, and old fracture had a substantially increased risk of any fracture (hazard ratio [HR] adjusted for age and sex 2.11, 95% confidence interval [CI] 2.08-2.14; HR 2.24, 95% CI 2.21-2.27; and HR 1.77, 95% CI 1.76-1.78, respectively) compared with controls. All recent fractures, MOFs, and non-MOFs, as well as older fractures, increase the risk of subsequent fracture, suggesting that all recent fractures should be included in fracture liaison services and that case-finding strategies for those with older fractures may be warranted to prevent subsequent fractures. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Comparison of Fractures Among Older Adults Who Are Ambulatory vs Those Who Use Wheelchairs in Sweden.

Importance: Several diseases and conditions, such as cerebrovascular disease, arthritis, previous fractures, neurological diseases, or amputation, can result in severe immobility justifying wheelchair use for increased mobility. Immobility results in disuse osteoporosis and is considered a risk factor for fracture, although there are no large cohort studies that have investigated fracture risk in patients who use wheelchairs compared with an ambulatory control group. Objective: To investigate whether immobilized adults who used wheelchairs had a different risk of fracture and injurious falls compared with matched ambulatory controls. Design, Setting, and Participants: This retrospective cohort study compared patients who used wheelchairs and controls (propensity score matched 1:1 using 22 variables relating to anthropometrics, general condition, comorbidity, and fall and fracture risk), identified through a national database of adults 65 years or older who underwent a health evaluation (baseline) at Swedish health care facilities. Patients were followed up from January 1, 2007, to December 31, 2017, and data analysis was performed between June 1 and 30, 2022. Main Outcomes and Measures: Incident fracture, injurious falls without fracture, and deaths. Results: A total of 55 442 adults using wheelchairs were included in the analysis (mean [SD] age, 83.2 [8.3] years; 60.5% women). Those who used wheelchairs and the 55 442 matched controls were followed up for a median of 2.0 (IQR, 0.5-3.2) and 2.3 (IQR, 0.8-3.6) years, respectively. Patients who used wheelchairs had a lower risk of any fracture (hazard ratio [HR], 0.43 [95% CI, 0.41-0.44]), major osteoporotic fracture (HR, 0.32 [95% CI, 0.31-0.33]), and hip fracture (HR, 0.30 [95% CI, 0.28-0.32]) compared with the ambulatory controls, associations that were only marginally affected by multivariable (same as the matching variables) adjustment. The risk of fall injury was lower among those who used wheelchairs than among ambulatory controls (unadjusted HR for Cox proportional hazards models, 0.48 [95% CI, 0.47-0.50]) and remained highly similar after adjustments. Patients who used wheelchairs had a significantly increased risk of death (HR, 1.35 [95% CI, 1.33-1.36]) compared with controls. Association between wheelchair use and fracture outcomes and injurious falls, calculated using a Fine and Gray model with death as a competing risk, was similar to associations obtained using Cox proportional hazards regression for all fracture outcomes. Conclusions and Relevance: In this retrospective cohort study of older adults, wheelchair use was associated with a lower risk of fracture than observed in ambulatory controls. These findings suggest that immobility associated with wheelchair use should not be considered a risk factor for fracture.

Occurrence and relative risks for non-vertebral fractures in patients with ankylosing spondylitis compared with the general population: a register-based study from Sweden.

OBJECTIVES: To estimate the incidence of non-vertebral fractures in ankylosing spondylitis (AS) compared with the general population. METHODS: Nationwide register-based cohort study including patients with AS (n=11 611, 65% men, mean age 48 years), and matched general population controls (n=58 050). Five prespecified fracture outcomes: (1) non-vertebral; (2) fracture of the proximal humerus, distal forearm or hip; (3) proximal humerus; (4) distal forearm and (5) hip) were identified through register linkages with follow-up 2007-2016. We used Poisson regression to calculate incidence rates (IRs), number of fractures per 1000 person-years at risk and IR ratios (IRRs), overall and by sex and age. IRRs were adjusted for history of any prior fracture. RESULTS: IRs (men/women) for non-vertebral fracture in AS were 11.9 (95% CI 11.0 to 12.9)/14.5 (95% CI 13.1 to 16.1) and in controls 10.0 (95% CI 9.7 to 10.4)/11.8 (95% CI 11.1 to 12.4), IRR (men/women) 1.2 (95% CI 1.1 to 1.3)/1.2 (95% CI 1.1 to 1.4). IRs (men/women) for fractures of the humerus, forearm or hip in AS were 4.0 (95% CI 3.5 to 4.6)/6.3 (95% CI 5.4 to 7.3) and in controls 2.7 (95% CI 2.5 to 2.9)/5.5 (95% CI 5.1 to 6.0), IRR (men/women) 1.5 (95% CI 1.3 to 1.7)/1.1 (95% CI 0.9 to 1.3). IRRs were statistically significantly elevated in men with AS versus controls for forearm fracture (1.4 (95% CI 1.1 to 1.7)) and hip fracture (1.8 (95% CI 1.4 to 2.3)), whereas not in women with AS where the IRRs were 1.1 (95% CI 0.9 to 1.4) and 1.0 (95% CI 0.6 to 1.4). For humerus fracture, IRRs were 1.4 (95% CI 0.99 to 1.9) in men with AS versus controls and 1.1 (95% CI 0.8 to 1.6) in women. CONCLUSIONS: Both men and women with AS have a slightly higher risk of non-vertebral fractures than the general population. A statistically significantly higher risk of fractures of the proximal humerus, distal forearm or hip was found in men with AS in comparison to general population, where the relative risk was especially pronounced for hip fracture.

Recent sarcopenia definitions-prevalence, agreement and mortality associations among men: Findings from population-based cohorts.

BACKGROUND: The 2019 European Working Group on Sarcopenia in Older People (EWGSOP2) and the Sarcopenia Definitions and Outcomes Consortium (SDOC) have recently proposed sarcopenia definitions. However, comparisons of the performance of these approaches in terms of thresholds employed, concordance in individuals and prediction of important health-related outcomes such as death are limited. We addressed this in a large multinational assembly of cohort studies that included information on lean mass, muscle strength, physical performance and health outcomes. METHODS: White men from the Health Aging and Body Composition (Health ABC) Study, Osteoporotic Fractures in Men (MrOS) Study cohorts (Sweden, USA), the Hertfordshire Cohort Study (HCS) and the Sarcopenia and Physical impairment with advancing Age (SarcoPhAge) Study were analysed. Appendicular lean mass (ALM) was ascertained using DXA; muscle strength by grip dynamometry; and usual gait speed over courses of 2.4-6 m. Deaths were recorded and verified. Definitions of sarcopenia were as follows: EWGSOP2 (grip strength <27 kg and ALM index <7.0 kg/m2 ), SDOC (grip strength <35.5 kg and gait speed <0.8 m/s) and Modified SDOC (grip strength <35.5 kg and gait speed <1.0 m/s). Cohen's kappa statistic was used to assess agreement between original definitions (EWGSOP2 and SDOC). Presence versus absence of sarcopenia according to each definition in relation to mortality risk was examined using Cox regression with adjustment for age and weight; estimates were combined across cohorts using random-effects meta-analysis. RESULTS: Mean (SD) age of participants (n = 9170) was 74.3 (4.9) years; 5929 participants died during a mean (SD) follow-up of 12.1 (5.5) years. The proportion with sarcopenia according to each definition was EWGSOP2 (1.1%), SDOC (1.7%) and Modified SDOC (5.3%). Agreement was weak between EWGSOP2 and SDOC (κ = 0.17). Pooled hazard ratios (95% CI) for mortality for presence versus absence of each definition were EWGSOP2 [1.76 (1.42, 2.18), I2 : 0.0%]; SDOC [2.75 (2.28, 3.31), I2 : 0.0%]; and Modified SDOC [1.93 (1.54, 2.41), I2 : 58.3%]. CONCLUSIONS: There was low prevalence and poor agreement among recent sarcopenia definitions in community-dwelling cohorts of older white men. All indices of sarcopenia were associated with mortality. The strong relationship between sarcopenia and mortality, regardless of the definition, illustrates that identification of appropriate management and lifecourse intervention strategies for this condition is of paramount importance.

Risk of fracture in adults with type 2 diabetes in Sweden: A national cohort study.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is considered a risk factor for fracture but the evidence regarding the impact of T2DM on fracture risk is conflicting. The objective of the study was to determine if patients with T2DM have increased fracture risk and if T2DM-related risk factors could be identified. METHODS AND FINDINGS: In this national cohort study in Sweden, we investigated the risk of fracture in 580,127 T2DM patients, identified through the national diabetes register including from both primary care and hospitals, and an equal number of population-based controls without diabetes matched for age, sex, and county from 2007 to 2017. The mean age at entry was 66.7 years and 43.6% were women. During a median follow-up time of 6.6 (interquartile range (IQR) 3.1 to 9.8) years, patients with T2DM had a marginally but significantly increased risk of major osteoporotic fracture (MOF) (hazard ratio (HR) 1.01 (95% confidence interval [CI] 1.00 to 1.03)) and hip fracture (HR 1.06 (95% CI 1.04 to 1.08)) compared to controls, associations that were only minimally affected (HR 1.05 (95% CI 1.03 to 1.06) and HR 1.11 (95% CI 1.09 to 1.14), respectively) by multivariable adjustment (age, sex, marital status, and an additional 20 variables related to general morbidity, cardiovascular status, risk of falls, and fracture). In a multivariable-adjusted Cox model, the proportion of the risk for all fracture outcomes (Heller's R2) explained by T2DM was below 0.1%. Among the T2DM patients, important risk factors for fracture were a low BMI (<25 kg/m2), long diabetes duration (≥15 years), insulin treatment, and low physical activity. In total, 55% of the T2DM patients had none of these risk factors and a significantly lower fracture risk than their respective controls. The relatively short mean duration of T2DM and lack of bone density data, constitute limitations of the analysis. CONCLUSION: In this study, we observed only a marginally increased fracture risk in T2DM, a condition that explained less than 0.1% of the fracture risk. Consideration of the herein identified T2DM-related risk factors could be used to stratify T2DM patients according to fracture risk.

Adjusting conventional FRAX estimates of fracture probability according to the number of prior falls in the preceding year.

A greater propensity to falling is associated with higher fracture risk. This study provides adjustments to FRAX-based fracture probabilities accounting for the number of prior falls. INTRODUCTION: Prior falls increase subsequent fracture risk but are not currently directly included in the FRAX tool. The aim of this study was to quantify the effect of the number of prior falls on the 10-year probability of fracture determined with FRAX®. METHODS: We studied 21,116 women and men age 40 years or older (mean age 65.7 ± 10.1 years) with fracture probability assessment (FRAX®), self-reported falls for the previous year, and subsequent fracture outcomes in a registry-based cohort. The risks of death, hip fracture, and non-hip major osteoporotic fracture (MOF-NH) were determined by Cox proportional hazards regression for fall number category versus the whole population (i.e., an average number of falls). Ten-year probabilities of hip fracture and major osteoporotic fracture (MOF) were determined according to the number of falls from the hazards of death and fracture incorporated into the FRAX model for the UK. The probability ratios (number of falls vs. average number of falls) provided adjustments to conventional FRAX estimates of fracture probability according to the number of falls. RESULTS: Compared with the average number of falls, the hazard ratios for hip fracture, MOF-NH and death were lower than unity in the absence of a fall history. Hazard ratios increased progressively with an increasing number of reported falls. The probability ratio rose progressively as the number of reported falls increased. Probability ratios decreased with age, an effect that was more marked the greater the number of prior falls. CONCLUSION: The probability ratios provide adjustments to conventional FRAX estimates of fracture probability according to the number of prior falls.

Primary hyperparathyroidism and fracture probability.

The incidence of hip and major osteoporotic fracture was increased in patients with primary hyperparathyroidism even in patients not referred for parathyroidectomy. The risk of death was also increased which attenuated an effect on fracture probabilities. The findings argue for widening the indications for parathyroidectomy in mild primary hyperparathyroidism. INTRODUCTION: Primary hyperparathyroidism (PHPT) is associated with an increase in the risk of fracture. In FRAX, the increase in risk is assumed to be mediated by low bone mineral density (BMD). However, the risk of death is also increased and its effect on fracture probability is not known. OBJECTIVE: The aim of this study was to determine whether PHPT affects hip fracture and major osteoporotic fracture risk independently of bone mineral density (BMD) and whether this and any increase in mortality affects the assessment of fracture probability. METHODS: A register-based survey of patients with PHPT and matched controls in Denmark were identified from hospital registers. The incidence of death, hip fracture, and major osteoporotic fracture were determined for computing fracture probabilities excluding time after parathyroidectomy. The gradient of risk for fracture for differences in BMD was determined in a subset of patients and in BMD controls. The severity of disease was based on serum calcium and parathyroid hormone levels. RESULTS: We identified 6884 patients with biochemically confirmed PHPT and 68,665 matched population controls. On follow-up, excluding time after parathyroidectomy in those undergoing surgery, patients with PHPT had a higher risk of death (+52%), hip fracture (+48%), and major osteoporotic fracture (+36%) than population controls. At any given age, average 10-year probabilities of fracture were higher in patients with PHPT than population controls. The gradient of fracture risk with differences in BMD was similar in cases and controls. Results were similar when confined to patients not undergoing parathyroidectomy. Fracture probability decreased with the severity of disease due to an increase in mortality rather than fracture risk. CONCLUSION: The risk of hip and other major osteoporotic fracture is increased in PHPT irrespective of the disease severity. Fracture probability was attenuated due to the competing effect of mortality. The increased fracture risk in patients treated conservatively argues for widening the indications for parathyroidectomy in mild PHPT.