Race-specific FRAX models are evidence-based and support equitable care: a response to the ASBMR Task Force report on Clinical Algorithms for Fracture Risk.

Task Force on 'Clinical Algorithms for Fracture Risk' commissioned by the American Society for Bone and Mineral Research (ASBMR) Professional Practice Committee has recommended that FRAX® models in the US do not include adjustment for race and ethnicity. This position paper finds that an agnostic model would unfairly discriminate against the Black, Asian and Hispanic communities and recommends the retention of ethnic and race-specific FRAX models for the US, preferably with updated data on fracture and death hazards. In contrast, the use of intervention thresholds based on a fixed bone mineral density unfairly discriminates against the Black, Asian and Hispanic communities in the US. This position of the Working Group on Epidemiology and Quality of Life of the International Osteoporosis Foundation (IOF) is endorsed both by the IOF and the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO).

High physical activity is associated with greater cortical bone size, better physical function, and with lower risk of incident fractures independently of clinical risk factors in older women from the SUPERB study.

The Physical Activity Scale for the Elderly (PASE) is a validated test to assess physical activity in older people. It has not been investigated if physical activity, according to PASE, is associated with fracture risk independently from the clinical risk factors (CRFs) in FRAX, bone mineral density (BMD), comorbidity, and if such an association is due to differences in physical performance or bone parameters. The purpose of this study was to evaluate if PASE score is associated with bone characteristics, physical function, and independently predicts incident fracture in 3014 75-80-year-old women from the population-based cross-sectional SUPERB study. At baseline participants answered questionnaires, and underwent physical function tests, detailed bone phenotyping with dual x-ray absorptiometry, and high-resolution peripheral quantitative computed tomography. Incident fractures were x-ray verified. Cox regression models were used to assess the association between PASE score and incident fractures, with adjustments for CRFs, FN BMD and Charlson comorbidity index. Women were divided into quartiles according to PASE score. Quartile differences in bone parameters (1.56% for cortical volumetric BMD and 4.08% for cortical area, Q4 vs. Q1, p = 0.007 and p = 0.022, respectively) were smaller than quartile differences in physical performance (27% shorter timed up and go test, 52% longer one leg standing time, Q4 vs. Q1). During 8 years (median, range 0.20-9.9) of follow-up, 1077 women had any fracture, 806 a major osteoporotic fracture (MOF; spine, hip, forearm, humerus), and 236 a hip fracture. Women in Q4 had 30% lower risk of any fracture, 32% lower risk of MOF, and 54% lower risk of hip fracture, compared to women in Q1. These associations remained in fully adjusted models. In conclusion, high physical activity was associated with substantially better physical function and a lower risk of any fracture, MOF and hip fracture, independently of risk factors used in FRAX, FN BMD and comorbidity.

The Physical Activity Scale for the Elderly (PASE) is a test to assess physical activity in older people. The purpose of this study was to evaluate if physical activity, according to PASE, is associated with bone parameters, physical function, and independently predicts future fracture in 3014 75­80-year-old women from the population-based SUPERB study. At baseline participants answered questionnaires, underwent physical function tests and dual x-ray absorptiometry. Subsequent fractures were x-ray verified. Women were divided into quartiles according to PASE score (Q1 least and Q4 most physically active). Women in Q4 had 27% shorter timed up and go test and 52% longer one leg standing time compared with Q1. During 8 years of follow-up, 1077 women had any fracture, 806 a major osteoporotic fracture (MOF; spine, hip, forearm, humerus), and 236 a hip fracture. Women in Q4 had 30% lower risk of any fracture, 32% lower risk of MOF, and 54% lower risk of hip fracture, compared to women in Q1. These associations remained in models considering comorbidity, bone mineral density and clinical risk factors. In conclusion, high physical activity was independently associated with better physical function and a lower risk of any fracture.

Real-world effectiveness of osteoporosis screening in older Swedish women (SUPERB).

Older women diagnosed with osteoporosis and referred to their general practitioners (GPs) exhibited significantly higher osteoporosis treatment rates and a reduced fracture risk compared to non-osteoporotic women who were not referred to their GPs. OBJECTIVE: The objective of this study was to investigate treatment rates and fracture outcomes in older women, from a population-based study, 1) diagnosed with osteoporosis, with subsequent referral to their general practitioner (GP), 2) women without osteoporosis, without referral to their GP. METHODS: In total, 3028 women, 75-80 years old were included in the SUPERB cohort. At inclusion, 443 women were diagnosed with osteoporosis (bone mineral density (BMD) T-score ≤ -2.5) at the lumbar spine or hip, did not have current or recent osteoporosis treatment, and were referred to their GP for evaluation (referral group). The remaining 2585 women without osteoporosis composed the control group. Sensitivity analysis was performed on subsets of the original groups. Adjusted Cox regression (hazard ratios (HR) and 95 % confidence intervals (CI)) analyses were performed to investigate the risk of incident fractures and the incidence of osteoporosis treatment. RESULTS: Cox regression models, adjusted for age, sex, body mass index (BMI), smoking, alcohol, glucocorticoid use, previous fracture, parent hip fracture, secondary osteoporosis, rheumatoid arthritis, and BMD at the femoral neck, revealed that the risk of major osteoporotic fracture was significantly lower (HR = 0.81, 95 % CI [0.67-0.99]) in the referral group than in the controls. Similarly, the risk of hip fracture (HR = 0.69, [0.48-0.98]) and any fracture (HR = 0.84, [0.70-1.00]) were lower in the referral group. During follow-up, there was a 5-fold increase (HR = 5.00, [4.39-5.74]) in the prescription of osteoporosis medication in the referral group compared to the control group. CONCLUSION: Screening older women for osteoporosis and referring those with osteoporosis diagnosis was associated with substantially increased treatment rates and reduced risk of any fracture, MOF, and hip fracture, compared to non-osteoporotic women.

Limosilactobacillus reuteri 6475 and Prevention of Early Postmenopausal Bone Loss: A Randomized Clinical Trial.

Importance: Daily supplementation with the probiotic Limosilactobacillus reuteri ATCC PTA 6475 (L reuteri) vs placebo has previously been demonstrated to reduce bone loss in an estrogen deficiency mice model and older women, although the magnitude of the effect was small. We hypothesized that long-term treatment with L reuteri could result in clinically relevant skeletal benefits in postmenopausal osteoporosis. Objective: To evaluate whether daily supplementation with L reuteri vs placebo could reduce early postmenopausal bone loss and whether the effects remained or increased over time during 2 years of treatment. Design, Setting, and Participants: A double-blind, randomized, placebo-controlled clinical trial was conducted between December 4, 2019, and October 6, 2022, at a single center in Gothenburg, southwestern Sweden. Participants were recruited by online advertisements, and letters were sent to 10 062 women aged 50 to 60 years. Responding women (n = 752) underwent telephone screening, resulting in 292 women being invited to a screening visit. Of those who were screened, 239 women met all inclusion criteria and had no exclusion criteria. Interventions: Capsules with L reuteri in 2 doses, 5 × 108 (low dose) or 5 × 109 (high dose) colony-forming units, taken twice daily or placebo were administered. All capsules also included cholecalciferol, 200 IU. Main Outcomes and Measures: The primary outcome was the relative change in tibia total volumetric bone mineral density (vBMD) over 2 years. Secondary outcomes included relative change in areal BMD of the lumbar spine and total hip, bone turnover markers C-terminal telopeptide cross-links of collagen type I and type I procollagen intact N-terminal propeptide, as well as tibia trabecular bone volume fraction and cortical vBMD. Both intention-to-treat and per-protocol analyses were conducted. Results: A total of 239 postmenopausal women (median age, 55 [IQR, 53-56] years) were included. Tibia vBMD (primary outcome), hip and spine vBMD, and tibia cortical area and BMD decreased significantly in all groups, with no group-to-group differences (percent change tibia vBMD high dose vs placebo least-squares means, -0.08 [95 CI, -0.85 to 0.69] and low dose vs placebo least-squares means, -0.22 [95% CI, -0.99 to 0.55]). There were no significant treatment effects on any other predefined outcomes. A prespecified sensitivity analysis found a significant interaction between body mass index (BMI) and treatment effect at 2 years. No significant adverse effects were observed. Conclusions and Relevance: In this randomized clinical trial of 239 early postmenopausal women, supplementation with L reuteri had no effect on bone loss or bone turnover over 2 years. The observed interaction between BMI and treatment effect warrants further investigation. Trial Registration: ClinicalTrials.gov Identifier: NCT04169789.

The role of different physical function tests for the prediction of fracture risk in older women.

BACKGROUND: Physical function is an important risk factor for fracture. Previous studies found that different physical tests (e.g., one-leg standing [OLS] and timed up and go [TUG]) predict fracture risk. This study aimed to determine which physical function test is the most optimal independent predictor of fracture risk, together with clinical risk factors (CRFs) used in fracture risk assessment (FRAX) and bone mineral density (BMD). METHODS: In total, 2321 women out of the included 3028 older women, aged 77.7 ± 1.6 (mean ± SD), in the Sahlgrenska University Hospital Prospective Evaluation of Risk of Bone Fractures study had complete data on all physical function tests and were included in the analysis. At baseline, hand grip strength, OLS, TUG, walking speed and chair stand tests were performed. All incident fractures were confirmed by X-ray or review of medical records and subsequently categorized as major osteoporotic fractures (MOFs), hip fractures and any fracture. Multivariate Cox regression (hazard ratios [HRs] and 95% confidence intervals [CIs]) analyses were performed with adjustments for age, body mass index (BMI), FRAX CRFs, femoral neck BMD and all physical function tests as predictors both individually and simultaneously. Receiver operating characteristic (ROC) analyses and Fine and Gray analyses were also performed to investigate associations between physical function and incident fractures. RESULTS: OLS was the only physical function test to be significantly and independently associated with increased risk of any fracture (HR 1.13 [1.04-1.23]), MOF (HR 1.15 [1.04-1.26]) and hip fracture (HR 1.34 [1.11-1.62]). Adjusting for age, BMI, CRFs and femoral neck BMD did not materially alter these associations. ROC analysis for OLS, together with age, BMI, femoral neck BMD and CRFs, yielded area under the curve values of 0.642, 0.647 and 0.732 for any fracture, MOF and hip fracture, respectively. In analyses considering the competing risk of death, OLS was the only physical function test consistently associated with fracture outcomes (subhazard ratio [SHR] 1.10 [1.01-1.19] for any fracture, SHR 1.11 [1.00-1.22] for MOF and SHR 1.25 [1.03-1.50] for hip fracture). Walking speed was only independently associated with the risk of hip fracture in all Cox regression models and in the Fine and Gray analyses. CONCLUSIONS: Among the five physical function tests, OLS was independently associated with all fracture outcomes, even after considering the competing risk of death, indicating that OLS is the most reliable physical function test for predicting fracture risk in older women.

Predictive value of sarcopenia components for all-cause mortality: findings from population-based cohorts.

BACKGROUND: Low grip strength and gait speed are associated with mortality. However, investigation of the additional mortality risk explained by these measures, over and above other factors, is limited. AIM: We examined whether grip strength and gait speed improve discriminative capacity for mortality over and above more readily obtainable clinical risk factors. METHODS: Participants from the Health, Aging and Body Composition Study, Osteoporotic Fractures in Men Study, and the Hertfordshire Cohort Study were analysed. Appendicular lean mass (ALM) was ascertained using DXA; muscle strength by grip dynamometry; and usual gait speed over 2.4-6 m. Verified deaths were recorded. Associations between sarcopenia components and mortality were examined using Cox regression with cohort as a random effect; discriminative capacity was assessed using Harrell's Concordance Index (C-index). RESULTS: Mean (SD) age of participants (n = 8362) was 73.8(5.1) years; 5231(62.6%) died during a median follow-up time of 13.3 years. Grip strength (hazard ratio (95% CI) per SD decrease: 1.14 (1.10,1.19)) and gait speed (1.21 (1.17,1.26)), but not ALM index (1.01 (0.95,1.06)), were associated with mortality in mutually-adjusted models after accounting for age, sex, BMI, smoking status, alcohol consumption, physical activity, ethnicity, education, history of fractures and falls, femoral neck bone mineral density (BMD), self-rated health, cognitive function and number of comorbidities. However, a model containing only age and sex as exposures gave a C-index (95% CI) of 0.65(0.64,0.66), which only increased to 0.67(0.67,0.68) after inclusion of grip strength and gait speed. CONCLUSIONS: Grip strength and gait speed may generate only modest adjunctive risk information for mortality compared with other more readily obtainable risk factors.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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).