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.

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.

Cost-effectiveness intervention thresholds for romosozumab and teriparatide in the treatment of osteoporosis in the UK.

Sequential romosozumab-to-alendronate or sequential teriparatide-to-alendronate can be a cost-effective treatment option for postmenopausal women at very high risk of fracture. PURPOSE: To estimate the 10-year probability of a major osteoporotic fracture (MOF) at which sequential treatment with romosozumab or teriparatide followed by alendronate, compared with alendronate alone, becomes cost-effective in a UK setting. METHODS: A microsimulation model with a Markov structure was used to simulate fractures, costs, and quality-adjusted life years (QALYs), in women receiving sequential treatment with either romosozumab or teriparatide followed by alendronate, compared with alendronate alone. Patients aged 50 to 90 years with a recent MOF, hip or spine fracture were followed from the start of a 5-year treatment until the age of 100 years or death. The analysis had a healthcare perspective. Efficacy of romosozumab, teriparatide and alendronate was derived from phase III randomised controlled trials. Resource use and unit costs were derived from the literature. Cost-effectiveness intervention threshold (CEIT), defined as the 10-year probability of a major osteoporotic fracture at which treatment becomes cost-effective, was compared with clinically appropriate intervention thresholds for bone-forming treatment in women with very high fracture risk as recommended by the UK National Osteoporosis Guideline Group (NOGG). RESULTS: The base case analysis showed that sequential romosozumab-to-alendronate treatment was cost-effective from a 10-year MOF probability of 18-35% and above depending on age and site of sentinel fracture at a willingness to pay (WTP) of £30,000. For teriparatide-to-alendronate, treatment was cost-effective at a 10-year MOF probability of 27-57%. The results were sensitive to pricing of the drugs but relatively insensitive to treatment duration, romosozumab persistence assumptions, and site of sentinel fracture. The CEITs for romosozumab-to-alendronate treatment were lower than the clinical thresholds from the age of 70 years meaning that treatment could be considered both cost-effective and aligned with the NOGG treatment guidelines. By contrast, for teriparatide-to-alendronate the CEITs were higher than the clinical thresholds irrespective of age. However, cost-effective scenarios were found in the presence of strong clinical risk factors in addition to a recent sentinel fracture. CONCLUSION: The results of this study indicate that sequential romosozumab-to-alendronate or teriparatide-to-alendronate treatment can be a cost-effective treatment option for postmenopausal women at very high risk of fracture.

Sarcopenia definitions and their association with injurious falls in older Swedish women from the Sahlgrenska University Hospital Prospective Evaluation of Risk of Bone fractures (SUPERB) study.

Associations between different sarcopenia definitions and the risk of injurious falls were investigated in 75-80-year-old women in the Swedish SUPERB cohort. Only sarcopenia according to the Sarcopenia Definitions and Outcomes Consortium (SDOC) definition was associated with incident injurious falls with and without fractures in older women. PURPOSE: To investigate the association between three commonly used sarcopenia definitions and the risk of injurious falls in a population of older Swedish women. METHODS: A total of 2,883 75-80-year-old women with complete data on relevant sarcopenia definitions from the Swedish SUPERB cohort were studied. Sarcopenia was defined based on the Sarcopenia Definitions and Outcomes Consortium (SDOC: low handgrip strength and gait speed), revised European Working Group on Sarcopenia in Older People (EWGSOP2: low appendicular lean mass index (ALMI, dual-energy X-ray absorptiometry (DXA)-derived), appendicular lean mass (kg)/height (m2), hand grip strength (kg), or low chair stand time (s)), and Asian Working Group for Sarcopenia (AWGS: low ALMI and hand grip strength (kg) or low gait speed (m/s)). Questionnaires captured the occurrence of falls in the past 12 months. Incident injurious falls were identified using national registers. Cox regression (hazard ratios (HR) and 95% confidence intervals (CI)) analyses were performed without adjustment and after adjustment for age, body mass index, previous falls, and the Charlson comorbidity index. RESULTS: During a median (IQR) follow-up time of 7.06 (6.2-7.9) years, there were 491 injurious falls without fracture and 962 injurious falls when also including falls resulting in a fracture. Sarcopenia according to EWGSOP2 and AWGS was not associated with an increased risk of injurious falls. Individuals with sarcopenia defined by SDOC had a higher risk of injurious falls with and without fracture (HR 2.11; 95% CI, 1.63-2.73 and HR, 2.16; 95% CI, 1.55-3.02, respectively). CONCLUSION: Sarcopenia definitions confined to muscle function and strength such as SDOC, rather than including DXA-determined ALMI (EWGSOP2 and AWGS), are associated with incident injurious falls with and without fractures in older women.

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).

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.

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.

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.

Osteoporosis epidemiology using international cohorts.

PURPOSE OF REVIEW: To provide an update on the most important new cohort studies within osteoporosis and their bearing on clinical management and directions for future research. RECENT FINDINGS: We identified a collection of new observational cohort studies - including new reports from already established large cohorts - and intervention studies providing new insights into osteoporosis pathophysiology, risk finding, intervention, and treatment barriers. SUMMARY: Recent cohort studies in osteoporosis highlight the importance of timely identification and treatment of people who are at high risk of suffering osteoporotic fractures. Physical performance is a strong indicator of fracture risk and one that is tightly linked to a number of chronic conditions, not least inflammatory conditions like rheumatoid arthritis. Advances in case finding may involve opportunistic screening for low bone mineral density and vertebral fractures of radiology images obtained for other purposes, polygenic risk scores, and routinely collected medication and comorbidity information.

The association between peripheral arterial disease and risk for hip fractures in elderly men is not explained by low hip bone mineral density. Results from the MrOS Sweden study.

In this prospective study in Swedish elderly men, PAD based on an ABI < 0.9 was associated with an increased risk of hip fracture, independent of age and hip BMD. However, after further adjustments for comorbidity, medications, physical function, and socioeconomic factors, the association diminished and was no longer statistically significant. INTRODUCTION: To examine if peripheral arterial disease (PAD) is associated with an increased risk for hip fracture in men independent of hip BMD. METHODS: Ankle-brachial index (ABI) was assessed in the Swedish MrOS (Osteoporotic Fractures in Men) study, a prospective observational study including 3014 men aged 69-81 years at baseline. PAD was defined as ABI < 0.90. Incident fractures were assessed in computerized X-ray archives. The risk for hip fractures was calculated using Cox proportional hazard models. At baseline, BMD was assessed using DXA (Lunar Prodigy and Hologic QDR 4500) and functional measurements and blood samples were collected. Standardized questionnaires were used to collect information about medical history, falls, and medication. RESULTS: During 10 years of follow-up, 186 men had an incident hip fracture. The hazard ratio (HR) for hip fracture in men with PAD was 1.70 (95% CI 1.14-2.54), adjusted for age and study site. Additional adjustment for total hip BMD marginally affected this association (HR 1.64; 95% CI 1.10-2.45). In a final multivariate model, the HR attenuated to a non-significant HR 1.38 (95% CI 0.91-2.11) adjusted for age, site, hip BMD, BMI, falls, smoking, eGFR, handgrip strength, walking speed, former hip fracture, antihypertensive treatment, diabetes, education, and history of cardiovascular disease. CONCLUSION: This study suggests that PAD is associated with an increased risk for hip fracture independently of hip BMD in elderly Swedish men. However, the high frequency of comorbidity and lower physical performance among men with PAD might partly explain this association.

Adjusting conventional FRAX estimates of fracture probability according to the number of prior fractures.

The risk of a recurrent fragility fracture is high following a first fracture and higher still with more than one prior fracture. This study provides adjustments to FRAX-based fracture probabilities accounting for the number of prior fractures. INTRODUCTION: Prior fractures increase subsequent fracture risk. The aim of this study was to quantify the effect of the number of prior fractures on the 10-year probability of fracture determined with FRAX®. METHODS: The study used data from the Reykjavik Study fracture register that documented prospectively all fractures at all skeletal sites in a large sample of the population of Iceland. Ten-year probabilities of hip fracture and major osteoporotic fracture (MOF) were determined according to the number of prior osteoporotic fractures over a 20-year interval from the hazards of death and fracture. Fracture probabilities were also computed for a prior osteoporotic fracture irrespective of the number of previous fractures. The probability ratios provided adjustments to conventional FRAX estimates of fracture probability according to the number of prior fractures. RESULTS: Probability ratios to adjust 10-year FRAX probabilities of a hip fracture and MOF increased with the number of prior fractures but decreased with age in both men and women. Probability ratios were similar in men and women and for hip fracture and MOF. Mean probability ratios according to the number of prior fractures for all scenarios were 0.95, 1.08, 1.21 and 1.35, for 1,2, 3 and 4 or more prior fractures, respectively. Thus, a simple rule of thumb is to downward adjust FRAX-based fracture probabilities by 5% in the presence of a single prior fracture and to uplift probabilities by 10, 20 and 30% with a history of 2, 3 and 4 or more prior fractures, respectively. CONCLUSION: The probability ratios provide adjustments to conventional FRAX estimates of fracture probability according to the number of prior fractures.

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.

Menopausal hormone therapy reduces the risk of fracture regardless of falls risk or baseline FRAX probability-results from the Women's Health Initiative hormone therapy trials.

In a combined analysis of 25,389 postmenopausal women aged 50-79 years, enrolled in the two Women's Health Initiative hormone therapy trials, menopausal hormone therapy vs. placebo reduced the risk of fracture regardless of baseline FRAX fracture probability and falls history. INTRODUCTION: The aim of this study was to determine if the anti-fracture efficacy of menopausal hormone therapy (MHT) differed by baseline falls history or fracture risk probability as estimated by FRAX, in a combined analysis of the two Women's Health Initiative (WHI) hormone therapy trials. METHODS: A total of 25,389 postmenopausal women aged 50-79 years were randomized to receive MHT (n = 12,739) or matching placebo (n = 12,650). At baseline, questionnaires were used to collect information on falls history, within the last 12 months, and clinical risk factors. FRAX 10-year probability of major osteoporotic fracture (MOF) was calculated without BMD. Incident clinical fractures were verified using medical records. An extension of Poisson regression was used to investigate the relationship between treatment and fractures in (1) the whole cohort; (2) those with prior falls; and (3) those without prior falls. The effect of baseline FRAX probability on efficacy was investigated in the whole cohort. RESULTS: Over 4.3 ± 2.1 years (mean ± SD), MHT (vs. placebo) significantly reduced the risk of any clinical fracture (hazard ratio [HR] 0.72 [95% CI, 0.65-0.78]), MOF (HR 0.60 [95% CI, 0.53-0.69]), and hip fracture (0.66 [95% CI, 0.45-0.96]). Treatment was effective in reducing the risk of any clinical fracture, MOF, and hip fracture in women regardless of baseline FRAX MOF probability, with no evidence of an interaction between MHT and FRAX (p > 0.30). Similarly, there was no interaction (p > 0.30) between MHT and prior falls. CONCLUSION: In the combined WHI trials, compared to placebo, MHT reduces fracture risk regardless of FRAX probability and falls history in postmenopausal women.

Physical exercise is associated with beneficial bone mineral density and body composition in young adults with childhood-onset inflammatory bowel disease.

BACKGROUND: Patients with inflammatory bowel disease (IBD) have an increased risk of compromised bone mineral density (BMD) and body composition. There are limited data on the physical exercise (PE) habits of patients with childhood-onset IBD and on the associations between PE and BMD and body composition. PATIENTS AND METHODS: In total, 72 young adults with childhood-onset IBD and 1341 normative young adult controls answered questionnaires regarding PE [hours/week (h/w)] in the last 12 months. BMD and body composition were measured with dual x-ray absorptiometry (DXA) and presented as age- and gender-adjusted Z-scores for BMD, skeletal muscle index (SMI, the weight of lean mass in arms and legs/m2), and percentage body fat (Fat %). RESULTS: A total of 41 (57%) patients with IBD engaged in PE during the previous 12 months, as compared to 913 (68%) of the controls (p = .053). Sedentary patients had significantly lower median BMD, SMI, and Fat % Z-scores than the controls with corresponding PE habits (all p < .05). In contrast, highly active (>4 h/week) patients had total body BMD, SMI, and Fat % in the same range as the controls with corresponding PE levels (p = .151, p = .992, and p = .189, respectively), albeit with lower BMDs in the spine (p = .007) and femoral neck (p = .015). Using multiple regression analyses, a diagnosis of childhood-onset IBD was independently associated with inferior BMD and body composition, regardless of the amount of PE. CONCLUSION: Physical exercise is associated with beneficial bone mineral density and body composition in patients with IBD despite the negative effects of the disease.

Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis.

Vitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide. Meta-analysis of the summary statistics from 19 cohorts identified in CYP2R1 the low-frequency (minor allele frequency = 2.5%) synonymous coding variant g.14900931G>A (p.Asp120Asp) (rs117913124[A]), which conferred a large effect on 25-hydroxyvitamin D (25OHD) levels (-0.43 SD of standardized natural log-transformed 25OHD per A allele; p value = 1.5 × 10-88). The effect on 25OHD was four times larger and independent of the effect of a previously described common variant near CYP2R1. By analyzing 8,711 individuals, we showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.78-2.78, p = 1.26 × 10-12). Individuals carrying one copy of this variant also had increased odds of multiple sclerosis (OR = 1.4, 95% CI = 1.19-1.64, p = 2.63 × 10-5) in a sample of 5,927 case and 5,599 control subjects. In conclusion, we describe a low-frequency CYP2R1 coding variant that exerts the largest effect upon 25OHD levels identified to date in the general European population and implicates vitamin D in the etiology of multiple sclerosis.

Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis.

BACKGROUND: Romosozumab is a monoclonal antibody that binds to and inhibits sclerostin, increases bone formation, and decreases bone resorption. METHODS: We enrolled 4093 postmenopausal women with osteoporosis and a fragility fracture and randomly assigned them in a 1:1 ratio to receive monthly subcutaneous romosozumab (210 mg) or weekly oral alendronate (70 mg) in a blinded fashion for 12 months, followed by open-label alendronate in both groups. The primary end points were the cumulative incidence of new vertebral fracture at 24 months and the cumulative incidence of clinical fracture (nonvertebral and symptomatic vertebral fracture) at the time of the primary analysis (after clinical fractures had been confirmed in ≥330 patients). Secondary end points included the incidences of nonvertebral and hip fracture at the time of the primary analysis. Serious cardiovascular adverse events, osteonecrosis of the jaw, and atypical femoral fractures were adjudicated. RESULTS: Over a period of 24 months, a 48% lower risk of new vertebral fractures was observed in the romosozumab-to-alendronate group (6.2% [127 of 2046 patients]) than in the alendronate-to-alendronate group (11.9% [243 of 2047 patients]) (P<0.001). Clinical fractures occurred in 198 of 2046 patients (9.7%) in the romosozumab-to-alendronate group versus 266 of 2047 patients (13.0%) in the alendronate-to-alendronate group, representing a 27% lower risk with romosozumab (P<0.001). The risk of nonvertebral fractures was lower by 19% in the romosozumab-to-alendronate group than in the alendronate-to-alendronate group (178 of 2046 patients [8.7%] vs. 217 of 2047 patients [10.6%]; P=0.04), and the risk of hip fracture was lower by 38% (41 of 2046 patients [2.0%] vs. 66 of 2047 patients [3.2%]; P=0.02). Overall adverse events and serious adverse events were balanced between the two groups. During year 1, positively adjudicated serious cardiovascular adverse events were observed more often with romosozumab than with alendronate (50 of 2040 patients [2.5%] vs. 38 of 2014 patients [1.9%]). During the open-label alendronate period, adjudicated events of osteonecrosis of the jaw (1 event each in the romosozumab-to-alendronate and alendronate-to-alendronate groups) and atypical femoral fracture (2 events and 4 events, respectively) were observed. CONCLUSIONS: In postmenopausal women with osteoporosis who were at high risk for fracture, romosozumab treatment for 12 months followed by alendronate resulted in a significantly lower risk of fracture than alendronate alone. (Funded by Amgen and others; ARCH ClinicalTrials.gov number, NCT01631214 .).

Altered body composition profiles in young adults with childhood-onset inflammatory bowel disease.

Background: Patients with inflammatory bowel disease (IBD) often develop alterations in body composition in terms of their proportions of lean mass and fat mass, as well as reduced bone mineral density (BMD). However, there are limited data on the skeletal muscle index (SMI) and percentage fat (fat %) for young adults with childhood-onset IBD. Our aim was to investigate the body compositions of these patients, with the focus on SMI and fat %.Methods: Body composition was estimated by dual x-ray absorptiometry for 94 young adults with childhood-onset IBD aged 18-27 years, 65 of whom had ulcerative colitis. The Z-scores for SMI, fat %, and BMD were calculated using the normative data from 1,289 individuals with corresponding age. Based on the SMI and fat % Z-scores, each patient was classified as having a body composition profile that was: (i) normal; (ii) obese (fat % Z-score >1); (iii) myopenic (SMI Z-score < -1); or (iv) myopenic-obese.Results: A higher proportion of young adults with childhood-onset IBD had a body composition profile classified as myopenic (24%) or myopenic-obese (9%), as compared to the controls (myopenic [16%, p = .016]; myopenic-obese [2%, p = .002]). Patients with the myopenic or myopenic-obese profile had significantly lower total body BMD Z-scores (-1.3 ± 0.7 and -1.4 ± 0.9, respectively) than patients with the normal profile (-0.2 ± 1.1; p < .001 and p = .004, respectively). Diagnosis of IBD in childhood represented an additional risk for low BMD, regardless of SMI Z-score.Conclusion: Young adults with childhood-onset IBD have a high risk for having altered body composition traits.SummaryYoung adults with childhood-onset IBD carry a high risk for altered body composition traits. The myopenic and myopenic-obese body composition profiles were more frequently observed in patients with IBD than controls, and these profiles were strongly associated with low BMD.

Incidence of myocardial infarction and associated mortality varies by latitude and season: findings from a Swedish Registry Study.

BACKGROUND: We investigated whether the incidence of death following myocardial infarction (MI) varied by season and latitude in the Swedish population. METHODS: We studied deaths following MI from January 1987 to December 2009, using the Swedish National Cause of Death Register. County of residence was used to determine latitude and population density. An extension of Poisson regression was used to study the relationship between risk of death following MI with age, latitude, time (from 1987), population density and calendar days. RESULTS: Over the study period, there was a secular decrease in the incidence of MI-related death. In men, MI-related death incidence increased by 1.3% [95% confidence interval (CI) = 1.1-1.5] per degree of latitude (northwards). In women, MI-related death incidence increased by 0.6% (95% CI = 0.4-0.9) per degree of latitude. There was seasonal variation in the risk of MI-related death with peak values in the late winter and a nadir in the summer months in both the north and the south of Sweden. Findings were similar with incident MI as the outcome. CONCLUSIONS: The incidence of MI-related death varied markedly by season and latitude in Sweden, with summer months and more southerly latitude associated with lower rates than winter months and more northerly latitude.