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.

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).

One-year supplementation with Lactobacillus reuteri ATCC PTA 6475 counteracts a degradation of gut microbiota in older women with low bone mineral density.

Recent studies have shown that probiotic supplementation has beneficial effects on bone metabolism. In a randomized controlled trial (RCT) we demonstrated that supplementation of Lactobacillus reuteri ATCC PTA 6475 reduced bone loss in older women with low bone mineral density. To investigate the mechanisms underlying the effect of L. reuteri ATCC PTA 6475 on bone metabolism, 20 women with the highest changes (good responders) and the lowest changes (poor responders) in tibia total volumetric BMD after one-year supplementation were selected from our previous RCT. In the current study we characterized the gut microbiome composition and function as well as serum metabolome in good responders and poor responders to the probiotic treatment as a secondary analysis. Although there were no significant differences in the microbial composition at high taxonomic levels, gene richness of the gut microbiota was significantly higher (P < 0.01 by the Wilcoxon rank-sum test) and inflammatory state was improved (P < 0.05 by the Wilcoxon signed-rank test) in the good responders at the end of the 12-month daily supplementation. Moreover, detrimental changes including the enrichment of E. coli (adjusted P < 0.05 by DESeq2) and its biofilm formation (P < 0.05 by GSA) observed in the poor responders were alleviated in the good responders by the treatment. Our results indicate that L. reuteri ATCC PTA 6475 supplementation has the potential to prevent a deterioration of the gut microbiota and inflammatory status in elderly women with low bone mineral density, which might have beneficial effects on bone metabolism.

A new bone adhesive candidate- does it work in human bone? An ex-vivo preclinical evaluation in fresh human osteoporotic femoral head bone.

INTRODUCTION: The fixation of small intraarticular bone fragments is clinically challenging and an obvious first orthopaedic indication for an effective bone adhesive. In the present study the feasibility of bonding freshly harvested human trabecular bone with OsSticR, a novel phosphoserine modified cement, was evaluated using a bone cylinder model pull-out test and compared with a commercial fibrin tissue adhesive. METHODS: Femoral heads (n=13) were collected from hip fracture patients undergoing arthroplasty and stored refrigerated overnight in saline medium prior to testing. Cylindrical bone cores with a pre-inserted bone screw, were prepared using a coring tool. Each core was removed and glued back in place with either the bone adhesive (α-tricalcium phosphate, phosphoserine and 20% trisodium citrate solution) or the fibrin glue. All glued bones were stored in bone medium at 37°C. Tensile loading, using a universal testing machine (5 kN load cell), was applied to each core/head. For the bone adhesive, bone cores were tested at 2 (n=13) and 24 (n=11) hours. For the fibrin tissue adhesive control group (n=9), bone cores were tested exclusively at 2 hours. The femoral bone quality was evaluated with micro-CT. RESULTS: The ultimate pull-out load for the bone adhesive at 2 hours ranged from 36 to 171 N (mean 94 N, SD 42 N). At 24 hours the pull-out strength was similar, 47 to 198 N (mean 123 N, SD 43 N). The adhesive failure usually occurred through the adhesive layer, however in two samples, at 167 N and 198 N the screw pulled out of the bone core. The fibrin tissue adhesive group reached a peak force of 8 N maximally at 2 hours (range 2.8-8 N, mean 5.4 N, SD 1.6 N). The mean BV/TV for femoral heads was 0.15 and indicates poor bone quality. CONCLUSION: The bone adhesive successfully glued wet and fatty tissue of osteoporotic human bone cores. The mean ultimate pull-out force of 123 N at 24 hours corresponds to ∼ 300 kPa shear stress acting on the bone core. These first ex-vivo results in human bone are a promising step toward potential clinical application in osteochondral fragment fixation.

The outcome of an automated assessment of trabecular pattern in intraoral radiographs as a fracture risk predictor.

OBJECTIVES: This study aims to investigate if automated analyses of the trabecular pattern in intraoral radiographs independently contribute to fracture risk assessment when other risk factors incorporated in the Fracture Risk Assessment Tool (FRAX) are taken into account. A secondary aim is to explore the correlation between the automated trabecular pattern assessment in intraoral radiographs and Trabecular Bone Score (TBS). METHODS: A total of 567 intraoral radiographs from older females participating in a large population-based study (SUPERB) based in Gothenburg, Sweden, were selected to analyse trabecular pattern using semi-automated and fully automated software. Associations between trabecular pattern analysis and incident fractures were studied using Cox proportional hazard model, unadjusted and adjusted for FRAX risk factors (previous fracture, family history of hip fracture, smoking, corticosteroids, rheumatoid arthritis, without and with bone mineral density (BMD) of the femoral neck). In addition, the correlation between trabecular pattern analysis and TBS of the lumbar spine was investigated using Pearson correlation analysis. RESULTS: Neither the unadjusted nor the adjusted trabecular pattern analysis in intraoral radiographs was significantly associated with any fracture or major osteoporotic fracture (MOF). A weak correlation was found between semi-automated trabecular pattern analysis and TBS. No correlation was found between the fully automated trabecular pattern analysis and TBS. CONCLUSIONS: The present study shows that semi-automated and fully automated digital analyses of the trabecular pattern in intraoral radiographs do not contribute to fracture risk prediction. Furthermore, the study shows a weak correlation between semi-automated trabecular pattern analysis and TBS.

Development of a novel method to measure bone marrow fat fraction in older women using high-resolution peripheral quantitative computed tomography.

Bone marrow adipose tissue (BMAT) has been implicated in a number of conditions associated with bone deterioration and osteoporosis. Several studies have found an inverse relationship between BMAT and bone mineral density (BMD), and higher levels of BMAT in those with prevalent fracture. Magnetic resonance imaging (MRI) is the gold standard for measuring BMAT, but its use is limited by high costs and low availability. We hypothesized that BMAT could also be accurately quantified using high-resolution peripheral quantitative computed tomography (HR-pQCT). METHODS: In the present study, a novel method to quantify the tibia bone marrow fat fraction, defined by MRI, using HR-pQCT was developed. In total, 38 postmenopausal women (mean [standard deviation] age 75.9 [3.1] years) were included and measured at the same site at the distal (n = 38) and ultradistal (n = 18) tibia using both MRI and HR-pQCT. To adjust for partial volume effects, the HR-pQCT images underwent 0 to 10 layers of voxel peeling to remove voxels adjacent to the bone. Linear regression equations were then tested for different degrees of voxel peeling, using the MRI-derived fat fractions as the dependent variable and the HR-pQCT-derived radiodensity as the independent variables. RESULTS: The most optimal HR-pQCT derived model, which applied a minimum of 4 layers of peeled voxel and with more than 1% remaining marrow volume, was able to explain 76% of the variation in the ultradistal tibia bone marrow fat fraction, measured with MRI (p < 0.001). CONCLUSION: The novel HR-pQCT method, developed to estimate BMAT, was able to explain a substantial part of the variation in the bone marrow fat fraction and can be used in future studies investigating the role of BMAT in osteoporosis and fracture prediction.

The challenge of applying digital image processing software on intraoral radiographs for osteoporosis risk assessment.

OBJECTIVES: The purpose of this study was to evaluate rater agreement and the accuracy of a semi-automated software and its fully automated tool for osteoporosis risk assessment in intraoral radiographs. METHODS: A total of 567 intraoral radiographs was selected retrospectively from women aged 75-80 years participating in a large population-based study (SUPERB) based in Gothenburg, Sweden. Five raters assessed participants' risk of osteoporosis in the intraoral radiographs using a semi-automated software. Assessments were repeated after 4 weeks on 121 radiographs (20%) randomly selected from the original 567. Radiographs were also assessed by the softwares' fully automated tool for analysis. RESULTS: Overall interrater agreement for the five raters was 0.37 (95% CI 0.32-0.41), and for the five raters with the fully automated tool included as 'sixth rater' the overall Kappa was 0.34 (0.30-0.38). Intrarater agreement varied from moderate to substantial according to the Landis and Koch interpretation scale. Diagnostic accuracy was calculated in relation to reference standard for osteoporosis diagnosis which is T-score values for spine, total hip and femoral neck and presented in form of sensitivities, specificities, predictive values, likelihood ratios and odds ratios. All raters' mean sensitivity, including the fully automated tool, was 40,4% (range 14,3%-57,6%). Corresponding values for specificity was 69,5% (range 59,7%-90,4%). The diagnostic odds ratios ranged between 1 and 2.7. CONCLUSION: The low diagnostic odds ratio and agreement between raters in osteoporosis risk assessment using the software for analysis of the trabecular pattern in intraoral radiographs shows that more work needs to be done to optimise the automation of trabecular pattern analysis in intraoral radiographs.

Metabolic Alterations in Older Women With Low Bone Mineral Density Supplemented With Lactobacillus reuteri.

Osteoporosis and its associated fractures are highly prevalent in older women. Recent studies have shown that gut microbiota play important roles in regulating bone metabolism. A previous randomized controlled trial (RCT) found that supplementation with Lactobacillus reuteri ATCC PTA 6475 (L.reuteri) led to substantially reduced bone loss in older women with low BMD. However, the total metabolic effects of L. reuteri supplementation on older women are still not clear. In this study, a post hoc analysis (not predefined) of serum metabolomic profiles of older women from the previous RCT was performed to investigate the metabolic dynamics over 1 year and to evaluate the effects of L. reuteri supplementation on human metabolism. Distinct segregation of the L. reuteri and placebo groups in response to the treatment was revealed by partial least squares-discriminant analysis. Although no individual metabolite was differentially and significantly associated with treatment after correction for multiple testing, 97 metabolites responded differentially at any one time point between L. reuteri and placebo groups (variable importance in projection score >1 and p value <0.05). These metabolites were involved in multiple processes, including amino acid, peptide, and lipid metabolism. Butyrylcarnitine was particularly increased at all investigated time points in the L. reuteri group compared with placebo, indicating that the effects of L. reuteri on bone loss are mediated through butyrate signaling. Furthermore, the metabolomic profiles in a case (low BMD) and control population (high BMD) of elderly women were analyzed to confirm the associations between BMD and the identified metabolites regulated by L. reuteri supplementation. The amino acids, especially branched-chain amino acids, showed association with L. reuteri treatment and with low BMD in older women, and may serve as potential therapeutic targets. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Intermediate monocytes correlate with CXCR3+ Th17 cells but not with bone characteristics in untreated early rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is associated with development of generalized osteoporosis. Bone-degrading osteoclasts are derived from circulating precursor cells of monocytic lineage, and the intermediate monocyte population is important as osteoclast precursors in inflammatory conditions. T cells of various subsets are critical in the pathogenesis of both RA and associated osteoporosis, but so far, no studies have examined associations between circulating intermediate monocytes, T cell subsets and bone characteristics in patients with RA. The aim of this study was to investigate the frequency of intermediate monocytes in patients with untreated early rheumatoid arthritis (ueRA) compared to healthy controls (HC), and to explore the correlation between intermediate monocytes and a comprehensive panel of T helper cell subsets, bone density and bone microarchitecture in ueRA patients. METHODS: 78 patients with ueRA fulfilling the ACR/EULAR 2010 criteria were included and compared to 29 age- and sex-matched HC. Peripheral blood samples were obtained before start of treatment and proportions of monocyte subsets and CD4+ helper and regulatory T cell subsets were analyzed by flow cytometry. Bone densitometry was performed on 46 of the ueRA patients at inclusion using DXA and HR-pQCT. RESULTS: Flow cytometric analyses showed that the majority of ueRA patients had frequencies of intermediate monocytes comparable to HC. The intermediate monocyte population correlated positively with CXCR3+ Th17 cells in ueRA patients but not in HC. However, neither the proportions of intermediate monocytes nor CXCR3+ Th17 cells were associated with bone density or bone microarchitecture measurements. CONCLUSIONS: Our findings suggest that in early RA, the intermediate monocytes do not correlate with bone characteristics, despite positive correlation with circulating CXCR3+ Th17 cells. Future longitudinal studies in patients with longer disease duration are required to fully explore the potential of intermediate monocytes to drive bone loss in RA.

Low-level cadmium exposure is associated with decreased cortical thickness, cortical area and trabecular bone volume fraction in elderly men: The MrOS Sweden study.

It is well known that high-level exposure to cadmium can cause bone disease such as osteoporosis, osteomalacia and fractures. However, the effect of low-level exposure, as found in the general population (mainly derived from diet and smoking), has only been assessed recently. The aim of this study was to examine if cadmium exposure in the general Swedish population causes other bone changes than decreased areal bone mineral density as measured by traditional DXA technology, e.g. changes in microstructure and geometry, such as cortical thickness or area, cortical porosity and trabecular bone volume. The study population consisted of 444 men, aged 70-81 years at inclusion year 2002-2004, from the Swedish cohort of the Osteoporotic Fractures in Men Study (MrOS). Cadmium was analyzed in baseline urine samples (U-Cd). Different parameters of bone geometry and microstructure were measured at the distal tibia at follow-up in 2009, including examination with high-resolution peripheral quantitative computed tomography (HR-pQCT). Associations between bone parameters and U-Cd in tertiles were estimated in multivariable analyses, including potential confounding factors (age, smoking, BMI, and physical activity). We found significant associations between U-Cd and several bone geometry or microstructure parameters, with 9% lower cortical thickness (p = 0.03), 7% lower cortical area (p = 0.04), and 5% lower trabecular bone volume fraction (p = 0.02) in the third tertile of U-Cd, using the first tertile as the reference. Furthermore, significant negative associations were found between log-transformed U-Cd and cortical thickness, cortical area, trabecular number and trabecular bone volume fraction, and a significant positive association with trabecular separation. The results indicate that low-level Cd exposure in the general population has negative effects on both cortical and trabecular bone.

Grade 1 Vertebral Fractures Identified by Densitometric Lateral Spine Imaging Predict Incident Major Osteoporotic Fracture Independently of Clinical Risk Factors and Bone Mineral Density in Older Women.

Because prevalent vertebral fracture (VF) is a strong predictor of future fractures, they are important to identify in clinical practice as osteoporosis medications are effective and can be used to reduce fracture risk in postmenopausal women with VF. Lateral spine imaging (LSI) with dual-energy X-ray absorptiometry (DXA) can be used to diagnose VFs accurately but is not widespread in clinical practice. The prognostic value of grade 1 (20% to 25% compression) VFs diagnosed by LSI with DXA has been insufficiently studied. The aim of this study was to determine if grade 1 VF is associated with incident fracture in older women. Sahlgrenska University Hospital Prospective Evaluation of Risk of Bone Fractures (SUPERB) is a population-based study of 3028 older women from Gothenburg, Sweden. Included women were 75 to 80 years of age at baseline, answered questionnaires, and were scanned with DXA (Discovery A, Hologic, Waltham, MA, USA). LSI was used to diagnose VFs, which were classified using the Genant semiquantitative method. Cox regression models were used to estimate the association between VFs at baseline and X-ray-verified incident fractures, with adjustment for confounders. Women with a grade 1 VF (n = 264) or a grade 2-3 VF (n = 349) were compared with women without any fracture (n = 1482). During 3.6 years (median, interquartile range [IQR] 1.5 years) of follow-up, 260 women had any incident fracture and 213 a major osteoporotic fracture (MOF). Women with only grade 1 VF had increased risk of any fracture (hazard ratio [HR] = 1.67; 95% confidence interval [CI] 1.18-2.36) and MOF (HR = 1.86; 95% CI 1.28-2.72). For MOF, this association remained after adjustment for clinical risk factors and femoral neck bone mineral density (BMD). In conclusion, grade 1 VFs were associated with incident MOF, also after adjustment for clinical risk factors and BMD, indicating that all VF identified by DXA should be considered in the evaluation of fracture risk in older women. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research..

Association Between Cortical Bone Microstructure and Statin Use in Older Women.

Context: Treatment with statins has been associated with increased bone mineral density, but whether this association depends on differences in cortical or trabecular volumetric bone microstructure is unknown. Objective: The aim of this study was to investigate if treatment with statins is associated with bone microstructure and geometry in older women. Design Setting and Participants: Older women were included in a population-based study of 3028 women (mean age ± SD, 77.8 ± 1.6 years) from the greater Gothenburg area in Sweden. Information regarding medical history, medication, and lifestyle factors was obtained from validated questionnaires. Main Outcome: Bone geometry and microstructure were measured at the ultradistal and distal (14%) site of radius and tibia using high-resolution peripheral quantitative computed tomography. Results: The 803 women in the cohort who used statins had higher body weight, worse physical function, and more frequent cardiovascular disease and diabetes than nonusers (P < 0.05). Statin users had lower cortical porosity (radius, 2.2 ± 1.9 vs 2.5 ± 2.0%; tibia, 5.2 ± 2.4 vs 5.4 ± 2.5; P = 0.01), higher cortical bone density (radius, 1008 ± 39.1 vs 1001 ± 38.4 mg/cm3; tibia, 919 ± 42.6 vs 914 ± 41.5; P < 0.01), and greater cortical area (radius, 60.5 ± 9.6 vs 58.6 ± 9.7 mm2; tibia, 150.0 ± 23.6 vs 146.7 ± 23.8; P < 0.01) than nonusers after adjustment for a large number of confounders, including age, weight, smoking, other medications, and prevalent diseases. Conclusions: Use of statins was associated with better cortical bone characteristics in older women.

Cortical and trabecular bone microarchitecture as an independent predictor of incident fracture risk in older women and men in the Bone Microarchitecture International Consortium (BoMIC): a prospective study.

BACKGROUND: Although areal bone mineral density (aBMD) assessed by dual-energy x-ray absorptiometry (DXA) is the clinical standard for determining fracture risk, most older adults who sustain a fracture have T scores greater than -2·5 and thus do not meet the clinical criteria for osteoporosis. Importantly, bone fragility is due to low BMD and deterioration in bone structure. We assessed whether indices of high-resolution peripheral quantitative CT (HR-pQCT) were associated with fracture risk independently of femoral neck aBMD and the Fracture Risk Assessment Tool (FRAX) score. METHODS: We assessed participants in eight cohorts from the USA (Framingham, Mayo Clinic), France (QUALYOR, STRAMBO, OFELY), Switzerland (GERICO), Canada (CaMos), and Sweden (MrOS). We used Cox proportional hazard ratios (HRs) to estimate the association between HR-pQCT bone indices (per 1 SD of deficit) and incident fracture, adjusting for age, sex, height, weight, and cohort, and then additionally for femoral neck DXA aBMD or FRAX. FINDINGS: 7254 individuals (66% women and 34% men) were assessed. Mean baseline age was 69 years (SD 9, range 40-96). Over a mean follow-up of 4·63 years (SD 2·41) years, 765 (11%) participants had incident fractures, of whom 633 (86%) had femoral neck T scores greater than -2·5. After adjustment for age, sex, cohort, height, and weight, peripheral skeleton failure load had the greatest association with risk of fracture: tibia HR 2·40 (95% CI 1·98-2·91) and radius 2·13 (1·77-2·56) per 1 SD decrease. HRs for other bone indices ranged from 1·12 (95% CI 1·03-1·23) per 1 SD increase in tibia cortical porosity to 1·58 (1·45-1·72) per 1 SD decrease in radius trabecular volumetric bone density. After further adjustment for femoral neck aBMD or FRAX score, the associations were reduced but remained significant for most bone parameters. A model including cortical volumetric bone density, trabecular number, and trabecular thickness at the distal radius and a model including these indices plus cortical area at the tibia were the best predictors of fracture. INTERPRETATION: HR-pQCT indices and failure load improved prediction of fracture beyond femoral neck aBMD or FRAX scores alone. Our findings from a large international cohort of men and women support previous reports that deficits in trabecular and cortical bone density and structure independently contribute to fracture risk. These measurements and morphological assessment of the peripheral skeleton might improve identification of people at the highest risk of fracture. FUNDING: National Institutes of Health National Institute of Arthritis Musculoskeletal and Skin Diseases.

Normal Bone Microstructure and Density But Worse Physical Function in Older Women Treated with Selective Serotonin Reuptake Inhibitors, a Cross-Sectional Population-Based Study.

Depression in the elderly is today often treated with selective serotonin reuptake inhibitors (SSRIs) because of their favorable adverse effect profile. However, treatment with SSRIs is associated with increased risk of fractures. Whether this increased risk depends on reduced bone strength or increased fall risk due to reduced physical function is not certain. The aim was therefore to investigate if treatment with SSRIs is associated with impaired bone microstructure, bone density, or physical function in older women. From an ongoing population-based study, 1057 women (77.7 ± 1.5 years) were included. Validated questionnaires were used to assess information regarding medical history, medications, smoking, mental and physical health, and physical activity. Physical function was measured using clinically used tests: timed up and go, walking speed, grip strength, chair stand test, and one leg standing. Bone mineral density (BMD) was measured at the hip and spine with dual-energy X-ray absorptiometry (Hologic Discovery A). Bone geometry and microstructure were measured at the ultradistal and distal (14%) site of radius and tibia using high-resolution peripheral quantitative computed tomography (HR-pQCT; XtremeCT). Treatment with SSRIs was associated with higher BMD at the femoral neck, total hip, and lumbar spine, whereas no associations were found for any HR-pQCT-derived measurements. The use of SSRIs was associated with lower grip strength, walking speed, and fewer chair stand rises. These associations were valid also after adjustments for known risk factors for falls. Treatment with SSRIs was, independently of covariates, associated with worse physical function without any signs of inferior bone geometry and microstructure.

High Serum Serotonin Predicts Increased Risk for Hip Fracture and Nonvertebral Osteoporotic Fractures: The MrOS Sweden Study.

Because several studies have implicated serotonin as a regulator of bone mass, we here explore its potential association on fracture risk and falls, as on bone mineral density (BMD) and muscle strength, in humans. Serum levels of serotonin were analyzed in 950 men (aged 69 to 81 years), participating in the Gothenburg part of the population-based study MrOS Sweden. Men taking selective serotonin reuptake inhibitors (SSRIs) had a mean value of 31.2 µg/L compared with 159.4 µg/L in those not taking SSRIs. SSRI users were excluded from further analysis. During 10-year follow-up, 224 men exhibited fractures, including 97 nonvertebral osteoporotic fractures (57 hip fractures), and 86 vertebral fractures. Serotonin was associated with hip fracture in linear analysis (hazard ratio [HR] = 1.27, 95% confidence interval [CI] 1.03-1.58) and to all fractures in a nonlinear manner, when quintiles of serotonin was included in quadratic terms (HR = 1.12, 95% CI 1.04-1.21). Men in serotonin quintile 5 had, in multivariable analysis, a HR of 2.30 (95% CI 1.31-4.02) for hip fracture and 1.82 (95% CI 1.17-2.85) for nonvertebral fractures compared with men in quintiles 1 to 4. Men in quintile 1 had, in multivariable analysis, a HR of 1.76 (95% CI 1.03-2.99) for nonvertebral fractures compared with men in quintiles 2 to 4. No association was found with vertebral fractures. Individuals in serotonin quintile 1 had higher prevalence of falls compared with quintiles 2 to 5 (odds ratio = 1.90, 95% CI 1.26-2.87). Serotonin was positively associated with hand-grip strength (r = 0.08, p = 0.02) and inversely with hip BMD (r = -0.10, p = 0.003). To assess the association between SSRIs and falls and fractures, the total MrOS Sweden cohort was examined (n = 3014). SSRI users (n = 90) had increased prevalence of falls (16% versus 33%, p = 0.0001) and increased rate of incident fractures (28.0 versus 44.7 per 1000 person-years, p = 0.018). We present novel data showing that high levels of serotonin predict an increased risk for hip fracture and nonvertebral osteoporotic fractures. © 2018 American Society for Bone and Mineral Research.

High-Impact Mechanical Loading Increases Bone Material Strength in Postmenopausal Women-A 3-Month Intervention Study.

Bone adapts to loading in several ways, including redistributing bone mass and altered geometry and microarchitecture. Because of previous methodological limitations, it is not known how the bone material strength is affected by mechanical loading in humans. The aim of this study was to investigate the effect of a 3-month unilateral high-impact exercise program on bone material properties and microarchitecture in healthy postmenopausal women. A total of 20 healthy and inactive postmenopausal women (aged 55.6 ± 2.3 years [mean ± SD]) were included and asked to perform an exercise program of daily one-legged jumps (with incremental number, from 3×10 to 4×20 jumps/d) during 3 months. All participants were asked to register their performed jumps in a structured daily diary. The participants chose one leg as the intervention leg and the other leg was used as control. The operators were blinded to the participant's choice of leg for intervention. The predefined primary outcome was change in bone material strength index (BMSi), measured at the mid tibia with a handheld reference probe indentation instrument (OsteoProbe). Bone microstructure, geometry, and density were measured with high-resolution peripheral quantitative computed tomography (XtremeCT) at the ultradistal and at 14% of the tibia bone length (distal). Differences were analyzed by related samples Wilcoxon signed rank test. The overall compliance to the jumping program was 93.6%. Relative to the control leg, BMSi of the intervention leg increased 7% or 0.89 SD (p = 0.046), but no differences were found for any of the XtremeCT-derived bone parameters. In conclusion, a unilateral high-impact loading program increased BMSi in postmenopausal women rapidly without affecting bone microstructure, geometry, or density, indicating that intense mechanical loading has the ability to rapidly improve bone material properties before changes in bone mass or structure. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

The Prevalence of Vertebral Fractures Is Associated With Reduced Hip Bone Density and Inferior Peripheral Appendicular Volumetric Bone Density and Structure in Older Women.

Vertebral fractures (VFs) are among the most severe and prevalent osteoporotic fractures. Their association with bone microstructure have been investigated in several retrospective case-control studies with spine radiography for diagnosis of VF. The aim of this population-based cross-sectional study of 1027 women aged 75 to 80 years was to investigate if prevalent VF, identified by vertebral fracture assessment (VFA) by dual-energy X-ray absorptiometry (DXA), was associated with appendicular volumetric bone density, structure, and bone material strength index (BMSi), independently of hip areal bone mineral density (aBMD). aBMD was measured using DXA (Discovery; Hologic); BMSi with microindentation (Osteoprobe); and bone geometry, volumetric BMD, and microstructure with high-resolution peripheral quantitative computed tomography (HRpQCT) (XtremeCT; Scanco Medical AG). aBMD was lower (spine 3.2%, total hip [TH] 3.8%) at all sites in women with VF, but tibia BMSi did not differ significantly compared to women without VF. In multivariable adjusted logistic regression models, radius trabecular bone volume fraction and tibia cortical area (odds ratio [OR] 1.26; 95% confidence interval [CI], [1.06 to 1.49]; and OR 1.27 [95% CI, 1.08 to 1.49], respectively) were associated with VF prevalence, whereas BMSi and cortical porosity were not. The risk of having one, two, or more than two VFs was increased 1.27 (95% CI, 1.04 to 1.54), 1.83 (95% CI, 1.28 to 2.61), and 1.78 (95% CI, 1.03 to 3.09) times, respectively, for each SD decrease in TH aBMD. When including either cortical area, trabecular bone volume fraction or TBS in the model together with TH aBMD and covariates, only TH aBMD remained independently associated with presence of any VF. In conclusion, TH aBMD was consistently associated with prevalent VFA-verified VF, whereas neither trabecular bone volume fraction, cortical area, cortical porosity, nor BMSi were independently associated with VF in older women. © 2017 American Society for Bone and Mineral Research.

Vertebral fractures and their association with health-related quality of life, back pain and physical function in older women.

Studies investigating prevalent vertebral fracture (VF) diagnosed using densitometry-based VF assessment (VFA) and associations with physical function, assessed by performance-based measures, are lacking. In this population-based study of 1027 older women, we found that prevalent VF, identified by VFA, was associated with inferior physical health, back pain and inferior physical function. PURPOSE: Several studies have investigated the associations between health-related quality of life (HRQL) and back pain with prevalent VF, detected by spine radiographs, but just a few have been population-based and have used vertebral fracture assessment (VFA) for diagnosing VF. The aims of this study were to investigate associations between prevalent VF, detected by VFA, with HRQL, back pain and physical function, and investigate if also mild VFs were associated with these clinical parameters. METHODS: One thousand twenty-seven women aged 75-80 years participated in this population-based cross-sectional study. VF was identified by VFA using dual-energy X-ray absorptiometry. HRQL was assessed by SF-12, back pain during the past 12 months using a questionnaire, and physical function was tested with one leg standing (OLS), Timed Up and Go (TUG), walking speed, 30-s chair stand test and maximum grip strength. RESULTS: Physical health (Physical Component Summary, PCS), derived from SF-12, was worse (43.5 ± 11.3 vs. 46.2 ± 10.5, p < 0.001) and back pain more frequent in women with any VF than in women without (69.0 vs. 59.9%, p = 0.008). PCS and physical function (OLS, 30-s chair stand test), were significantly worse for mild VF compared to no VF (43.8 ± 10.9 vs. 46.2 ± 10.5, p < 0.001, 12.7 ± 9.9 vs. 15.3 ± 10.4 s, p = 0.038, 10.7 ± 3.2 vs. 11.4 ± 3.4 times, p = 0.021, respectively). In multivariable adjusted linear regression models, VF prevalence was associated with PCS (ß = - 0.079, p = 0.007), TUG (ß = 0.067, p = 0.021), walking speed (ß = - 0.071, p = 0.009) and 30-s chair stand test (ß = - 0.075, p = 0.012). CONCLUSIONS: In conclusion, prevalent VF, diagnosed by VFA, was associated with inferior physical health, back pain and inferior physical function, indicating VFA is useful for diagnosing clinically relevant vertebral fractures. Also, mild VF was associated with inferior physical health and inferior physical function.