Geographic variation in bone mineral density and prevalent fractures in the Canadian longitudinal study on aging.

Awareness of the prevalence of osteoporosis and fractures across jurisdictions can guide the development of local preventive programs and healthcare policies. We observed geographical variations in total hip bone mineral density and in the prevalence of major osteoporotic fractures across Canadian provinces, which persisted after adjusting for important covariates. PURPOSE: We aimed to describe sex-specific total hip bone mineral density (aBMD) and prevalent major osteoporotic fractures (MOF) variation between Canadian provinces. METHODS: We used baseline data from 21,227 Canadians (10,716 women, 10,511 men) aged 50-85 years in the Canadian Longitudinal Study on Aging (CLSA; baseline: 2012-2015). Linear and logistic regression models were used to examine associations between province of residence and total hip aBMD and self-reported MOF, stratified by sex. CLSA sampling weights were used to generate the prevalence and regression estimates. RESULTS: The mean (SD) age of participants was 63.9 (9.1) years. The mean body mass index (kg/m2) was lowest in British Columbia (27.4 [5.0]) and highest in Newfoundland and Labrador (28.8 [5.3]). Women and men from British Columbia had the lowest mean total hip aBMD and the lowest prevalence of MOF. Alberta had the highest proportion of participants reporting recent falls (12.0%), and Manitoba (8.4%) the fewest (p-value=0.002). Linear regression analyses demonstrated significant differences in total hip aBMD: women and men from British Columbia and Alberta, and women from Manitoba and Nova Scotia had lower adjusted total hip aBMD than Ontario (p-values<0.02). Adjusted odds ratios (95% confidence intervals, CI) for prevalent MOF were significantly lower in women from British Columbia (0.47 [95% CI: 0.32; 0.69]) and Quebec (0.68 [95% CI: 0.48; 0.97]) and in men from British Columbia (0.40 [95% CI:0.22; 0.71]) compared to Ontario (p-values<0.03). Results were similar when adjusting for physical performance measures and when restricting the analyses to participants who reported White race/ethnicity. CONCLUSION: Geographical variations in total hip aBMD and in the prevalence of MOF between provinces persisted after adjusting for important covariates which suggests an association with unmeasured individual and environmental factors.

Electron microscopy approach to the wetting dynamics of single organosilanized mesopores.

Columnar mesoporous silicon (PSi) with hydrophobic vs. hydrophilic chemistries was chosen as a model for the local (pore-by-pore) study of water-pore interactions. Tomographic reconstructions provided a 3D view of the ramified pore structure. An in situ study of PSi wetting was conducted for categorized pore diameters by environmental scanning TEM. An appropriate setting of the contrast allows for the normalization of the gray scale in the images as a function of relative humidity (RH). This allows constructing an isotherm for each single pore and a subsequent averaging provides an isotherm for each pore size range. The isotherms systematically point to an initial adsorption through the formation of water adlayers, followed by a capillary filling process at higher RH. The local isotherms correlate with (global) gravimetric determination of wetting. Our results point at the validation of a technique for the study of aging and stability of single-pore nanoscale devices.

A new diatom-based multimetric index to assess lake ecological status.

Eutrophication impairs lake ecosystems at a global scale. In this context, as benthic microalgae are well-established warnings for a large range of stressors, particularly nutrient enrichment, the Water Framework Directive required the development of diatom-based methods to monitor lake eutrophication. Here, we present the diatom-based index we developed for French lakes, named IBDL (Indice Biologique Diatomées en Lacs). Data were collected in 93 lakes from 2015 to 2020. A challenge arose from the discontinuous pressure gradient of our dataset, especially the low number of nutrient-impacted lakes. To analyze the data we opted for the so-called "Threshold Indicator Taxa ANalysis" method, which makes it possible to determine a list of "alert taxa." We obtained a multimetric index based on specific pressure gradients (Kjeldahl nitrogen, suspended matter, biological oxygen demand, and total phosphorous). Considering the European intercalibration process, the very good correlation between IBDL and the common metric (R2 from 0.52 to 0.87 according to the lake alkalinity type) makes us very confident in our ability to match future IBDL quality thresholds with European standards. The IBDL proved at last to be particularly relevant as it has a twofold interest: an excellent relationship with total phosphorus (R2 from 0.63 to 0.83 according to the lake alkalinity type) and a possible application to any lake metatype. Its complementarity with macrophyte-based indices moreover justifies the use of at least two primary producer components for lake ecological status classification.

International consensus on the non-pharmacological and non-surgical management of osteoporotic vertebral fractures.

We identified a knowledge gap in the non-pharmacological and non-surgical management of osteoporotic vertebral fractures. MAIN RESULTS: This international consensus process established multidisciplinary biopsychosocial recommendations on pain, nutrition, safe movement, and exercise for individuals with acute and chronic vertebral fractures. SIGNIFICANCE: These recommendations will guide clinical practice and inform interventions for future research. PURPOSE: To establish international consensus on recommendations for the non-pharmacological and non-surgical management of osteoporotic vertebral fractures. METHODS: We adopted a five-step modified Delphi consensus process: (1) literature search and content analysis, (2) creation of the survey, (3) selection of the expert panel, (4) first round of the rating process, and (5) second round of the rating process. The first round included 49 statements and eight open-ended questions; the second round included 30 statements. Panelists were asked to rate their agreement with each of the statements using a 9-point scale, with the option to provide further comments. Consensus for each statement was determined by counting the number of panelists whose rating was outside the 3-point region containing the median. RESULTS: We invited 76 people with degree in medicine, physiotherapy, kinesiology, and experience in the management of osteoporotic vertebral; 31 (41%) and 27 (36%) experts agreed to participate to the first and the second round, respectively. The mean percentage agreement after the first and second rounds was 76.6% ± 16.0% and 90.7% ± 6.5%, respectively. We established consensus on recommendations on pain, early satiety, weight loss, bracing, safe movement, and exercise for individuals with acute and chronic vertebral fractures. CONCLUSION: Our international consensus provides multidisciplinary biopsychosocial recommendations to guide the management of osteoporotic vertebral fractures and inform interventions for future research.

Should vertebral fracture assessment be performed in Fracture Liaison Service patients with non-vertebral fracture?

Prior non-vertebral fractures, except of the ankle, are associated with increased likelihood of vertebral fracture. As knowledge of vertebral fracture presence may alter care, vertebral fracture assessment (VFA) is indicated in patients with prior fracture. INTRODUCTION: Vertebral fractures are often unappreciated. It was recently advocated that all Fracture Liaison Service (FLS) patients have densitometric VFA performed. We evaluated the likelihood of vertebral fracture identification with VFA in patients with prior fracture using the Manitoba Bone Density database. METHODS : VFA was performed in patients with T-scores below - 1.5 and age 70 + (or younger with height loss or glucocorticoid use) obtaining bone densitometry in Manitoba from 2010 to 2018. Those with prior clinical vertebral fracture, pathologic fracture, or uninterpretable VFA were excluded. Vertebral fractures were identified using the modified ABQ method. Health records were assessed for non-vertebral fracture (excluding head, neck, hand, foot) diagnosis codes unassociated with trauma prior to DXA. Multivariable odds ratios (ORs) for vertebral fracture were estimated without and with adjustment for age, sex, body mass index, ethnicity, area of residence, income level, comorbidity score, diabetes mellitus, falls in the last year, glucocorticoid use, and lowest BMD T-score. RESULTS: The study cohort consisted of 12,756 patients (94.4% women) with mean (SD) age 75.9 (6.8) years. Vertebral fractures were identified in 1925 (15.1%) overall. Vertebral fractures were significantly more likely (descending order) in those with prior pelvis, hip, humerus, other sites, and forearm, but not ankle fracture. There was modest attenuation with covariate adjustment but statistical significance was maintained. CONCLUSIONS: Prior hip, humerus, pelvis, forearm, and other fractures are associated with an increased likelihood of previously undiagnosed vertebral fracture, information useful for risk stratification and monitoring. These data support recommending VFA in FLS patients who are age 70 + with low BMD.

Time since prior fracture affects mortality at the time of clinical assessment: a registry-based cohort study.

Fractures are associated with increased long-term mortality in patients surviving to undergo baseline DXA. Notably, excess mortality risk does not decline with increasing time since prior hip or humerus fractures, even after accounting for comorbid medical conditions and other risk factors. INTRODUCTION: Mortality risk increases following most types of fracture. In routine clinical practice, patients with prior fractures seen for dual-energy X-ray absorptiometry scan (DXA) are "survivors;" whether they remain at increased mortality risk is unknown. We tested the association between prior fracture and all-cause mortality, stratified by time since fracture, in patients undergoing baseline DXA. METHODS: We conducted a DXA registry-based cohort study and linked to population-based health services data for the Province of Manitoba, Canada. We identified women and men ≥ 40 years with minimum 10 years of prior healthcare coverage undergoing baseline DXA and ascertained prior fracture codes since 1984 and mortality to 2017. Time since prior fracture was calculated between the clinical encounter for the fracture and baseline DXA (index date). Cox proportional hazards models estimated hazard ratios for all-cause mortality in those with compared to those without prior fracture adjusted for (1) age and sex, and (2) age, sex, comorbidities, and other covariates. RESULTS: The study cohort consisted of 74,474 individuals (mean age 64.6 years, 89.7% female). During mean follow-up 9.2 years, we ascertained 14,923 (20.0%) deaths. Except for forearm fractures, all fracture sites were associated with increased mortality risk compared to those without prior fracture, even after multivariable adjustment. Excess mortality risk tended to decline slightly with time since fracture and was no longer significant > 10 years after vertebral fracture. However, excess mortality persisted > 10 years following hip or humerus fracture. CONCLUSIONS: Prior fractures are associated with increased long-term mortality in patients surviving to undergo baseline DXA. Excess mortality risk does not decline with time since prior hip or humerus fractures, after accounting for potential confounders. Fracture prevention may have important long-term benefits preserving life expectancy.

Time dependency in early major osteoporotic and hip re-fractures in women and men aged 50 years and older: a population-based observational study.

We analyzed patterns in recurrent major osteoporotic fracture (MOF) following a first major osteoporotic fracture in a large population-based cohort. Re-fracture risk remained elevated over 10 years, with only modest and inconsistent attenuation in risk over time. INTRODUCTION: Recurrent fracture risk remains elevated for up to 25 years, and is reportedly highest in the initial 2 years (imminent risk). Our aim was to characterize early time dependency in re-fracture rates up to 10 years after a first fracture in a population-based cohort. METHODS: Using Province of Manitoba (Canada) healthcare databases, we performed a matched cohort study in 22,105 women (mean age 74.1 ± 10.6 years) and 7589 men (mean age 71.8 ± 11.2 years) after a first MOF (age ≥ 50 years) during 1989-2006 and matched fracture-free controls (3 for each case). Incident fractures were ascertained over the next 10 years. Fracture rate ratios (RRs, cases versus controls) stratified by sex and age were computed, and tested for linear trend using linear regression. Joinpoint regression was performed to determine non-linear change in fracture rates over time, with particular attention to the first 2-year post-fracture. RESULTS: RRs for incident MOF and hip fracture exceeded unity for the primary analyses in all subgroups and follow-up intervals. There was a tendency of RRs to decline over time, but this was inconsistent. Absolute rates per 100,000 person-years for fracture cases were consistently greater than for controls in all subgroups and observation times. Among fracture cases, there was a tendency for rates to decline gradually in all subgroups except younger women, but these temporal trends appeared monotonic without an inflection at 2 years. Joinpoint regression analyses did not detect an inflection in risk between the first 2 years and subsequent years. No significant time dependency was seen for incident hip fracture. CONCLUSIONS: MOF and hip re-fracture risk was elevated in all age and sex subgroups over 10 years. There was inconsistent and only modest time dependency in early MOF risk, most evident in women after age 65 years. No strong transition in risk was seen between the first 2-year post-fracture and subsequent years.

Predictive performance of the Garvan Fracture Risk Calculator: a registry-based cohort study.

The G arvan Fracture Risk Calculator predicts risk of osteoporotic fractures. We evaluated its predictive performance in 16,682 women and 2839 men from Manitoba, Canada, and found significant risk stratification, with a strong gradient across scores. The tool outperformed clinical risk factors and bone mineral density for fracture risk stratification. INTRODUCTION: The optimal model for fracture risk estimation to guide treatment decision-making remains controversial. Our objective was to evaluate the predictive performance of the Garvan Fracture Risk Calculator (FRC) in a large clinical registry from Manitoba, Canada. METHODS: Using the population-based Manitoba Bone Mineral Density (BMD) registry, we identified women and men aged 50-95 years undergoing baseline BMD assessment from September 1, 2012, onwards. Five-year Garvan FRC predictions were generated from clinical risk factors (CRFs) with and without femoral neck BMD. We identified incident non-traumatic osteoporotic fractures (OFs) and hip fractures (HFs) from population-based healthcare data sources to March 31, 2018. Fracture risk was assessed from area under the receiver operating characteristic curve (AUROC). Cox regression analysis and calibration ratios (5-year observed/predicted) were assessed for risk quintiles. All analyses were sex stratified. RESULTS: We included 16,682 women (mean age 66.6 + / - SD 8.7 years) and 2839 men (mean age 68.7 + / - SD 10.2 years). During a mean observation time of 2.6 years, incident OFs were identified in 681 women and 140 men and HFs in 199 women and 22 men. AUROC showed significant fracture risk stratification with the Garvan FRC. Tool predictions without BMD were better than from age or decreasing weight, and the tool with BMD performed better than BMD alone. Garvan FRC with BMD performed better than without BMD, especially for HF prediction (AUROC 0.86 in women, 0.82 in men). There was a strong gradient of increasing risk across Garvan FRC quintiles (highest versus lowest, hazard ratios women 5.75 and men 3.43 for any OF; women 101.6 for HF). Calibration differences were noted, with both over- and underestimation in risk. CONCLUSIONS: Garvan FRC outperformed CRFs and BMD alone for fracture risk stratification, particularly for HF, but may require recalibration for accurate predictions in this population.

Long-term risk of subsequent major osteoporotic fracture and hip fracture in men and women: a population-based observational study with a 25-year follow-up.

The risk of subsequent major osteoporotic and hip fracture following an initial fracture was increased in both sexes over 25 years, with modest time-dependent attenuation. This risk was highest in men, underscoring the importance of targeted treatment strategies particularly in this under-treated population. INTRODUCTION: The risk of subsequent fractures is increased following an index fracture, and declines over time. We aimed to determine whether this risk was sustained over 25 years and evolved similarly in men and women. METHODS: Using population-based databases, we performed a matched cohort study in 16,876 men and 39,230 women ≥ 50 years who sustained an index fracture during 1989-2006. Rates of subsequent major osteoporotic fractures (MOF) and hip fractures until 2016 were compared to rates for matched controls (n = 160,983). Age- and sex-stratified cumulative incidences to 25 years were estimated in the presence of competing mortality. Hazard ratios (HRs) with 95% confidence intervals (CI) for subsequent fractures were estimated for each on the first 15 years of follow-up with a final category ≥ 15 years, adjusted for comorbidities. RESULTS: Risk for MOF and hip fractures remained elevated up to 25 years in both sexes. The cumulative incidence of fractures was higher in cases vs controls in both sexes and across all age categories except in those > 90 years. Crude rate ratios for subsequent MOF were 2.5 (95% CI 2.3-2.7) in men and 1.6 (95% CI 1.6-1.7) in women and were higher in the younger age groups. Adjusted HRs (aHRs) for subsequent MOF were higher in men than in women in the first year (men aHR 2.6, 95% CI 2.1-3.3; women aHR 1.6, 95% CI 1.4-1.7). CONCLUSIONS: The risk of subsequent fractures following an initial fracture was increased over 25 years and the magnitude of risk was initially greater in men than in women.

Simulated effects of early menopausal bone mineral density preservation on long-term fracture risk: a feasibility study.

Prevention of early menopausal bone loss may reduce the future burden of osteoporosis. In this modelling exercise, an osteoporosis prevention strategy involving 5-year infusions of zoledronic acid, beginning early in menopause, reduced long-term fracture risk and the proportion of aging women with femoral neck densitometric osteoporosis. This strategy warrants further evaluation. INTRODUCTION: Preventing early menopausal bone loss may substantially reduce the future burden of osteoporosis. We modelled the effects of infrequent zoledronic acid infusions on long-term fracture risk. METHODS: Data from the Canadian Multicentre Osteoporosis Study (CaMos) were used to determine the expected natural history of femoral neck areal bone mineral density (BMD) and fracture risk (using FRAX®) from ages 50-80 for women with no antiresorptive drug exposures. We modelled the effects of three infusions of zoledronic acid (at ages 50, 55, 60) on long-term fracture risk, assuming this intervention would preserve BMD until age 65 years, followed by losses mirroring early menopausal BMD loss. RESULTS: At age 65, untreated women and zoledronic acid recipients had expected mean (SD) femoral neck T-scores of - 1.5(1.0) and - 0.8(1.0), 10-year major osteoporotic fracture (MOF) risks of 9.8%(5.0) and 8.0%(3.7) and hip fracture risks of 1.7%(2.4) and 0.8%(1.2), respectively. At age 80, untreated women and zoledronic acid recipients had expected femoral neck T-scores of - 1.9(0.9) and - 1.4(0.9), MOF risks of 17.9%(8.2) and 14.9%(6.4) and hip fracture risks of 6.3%(6.2) and 4.4%(4.5), respectively. The expected proportion of women with femoral neck T-score ≤ - 2.5 was 14.9% for untreated women and 3.8% for zoledronic acid recipients at age 65, increasing to 28.1% and 12.0%, respectively, at age 80. Numbers-needed-to-treat to prevent one case of densitometric osteoporosis were 9 at age 65 and 5 at age 80. CONCLUSION: Infrequent infusions of zoledronic acid, initiated early in menopause, are expected to reduce long-term fracture risk and result in a substantial reduction in the proportion of women with densitometric osteoporosis after age 65.

Overloaded! Critical revision and a new conceptual approach for snow indicators in ski tourism.

Indicators are widely used in climate variability and climate change assessments to simplify the tracking of complex processes and phenomena in the state of the environment. Apart from the climatic criteria, the snow indicators in ski tourism have been increasingly extended with elements that relate to the technical, operational, and commercial aspects of ski tourism. These non-natural influencing factors have gained in importance in comparison with the natural environmental conditions but are more difficult to comprehend in time and space, resulting in limited explanatory power of the related indicators when applied for larger/longer scale assessments. We review the existing indicator approaches to derive quantitative measures for the snow conditions in ski areas, to formulate the criteria that the indicators should fulfill, and to provide a list of indicators with their technical specifications which can be used in snow condition assessments for ski tourism. For the use of these indicators, a three-step procedure consisting of definition, application, and interpretation is suggested. We also provide recommendations for the design of indicator-based assessments of climate change effects on ski tourism. Thereby, we highlight the importance of extensive stakeholder involvement to allow for real-world relevance of the achieved results.

The association of objectively ascertained sibling fracture history with major osteoporotic fractures: a population-based cohort study.

We investigated the association of objectively ascertained sibling fracture history with major osteoporotic fracture (hip, forearm, humerus, or clinical spine) risk in a population-based cohort using administrative databases. Sibling fracture history is associated with increased major osteoporotic fracture risk, which has implications for fracture risk prediction. INTRODUCTION: We aimed to determine whether objectively ascertained sibling fracture history is associated with major osteoporotic fracture (MOF; hip, forearm, humerus, or clinical spine) risk. METHODS: This retrospective cohort study used administrative databases from the province of Manitoba, Canada, which has a universal healthcare system. The cohort included men and women 40+ years between 1997 and 2015 with linkage to at least one sibling. The exposure was sibling MOF diagnosis occurring after age 40 years and prior to the outcome. The outcome was incident MOF identified in hospital and physician records using established case definitions. A multivariable Cox proportional hazards regression model was used to estimate the risk of MOF after adjustment for known fracture risk factors. RESULTS: The cohort included 217,527 individuals; 91.9% were linked to full siblings (siblings having the same father and mother) and 49.0% were females. By the end of the study period, 6255 (2.9%) of the siblings had a MOF. During a median follow-up of 11 years (IQR 5-15), 5235 (2.4%) incident MOF were identified in the study cohort, including 234 hip fractures. Sibling MOF history was associated with an increased risk of MOF (hazard ratio [HR] 1.67, 95% confidence interval [CI] 1.44-1.92). The risk was elevated in both men (HR 1.57, 95% CI 1.24-1.98) and women (HR 1.74, 95% CI 1.45-2.08). The highest risk was associated with a sibling diagnosis of forearm fracture (HR 1.81, 95% CI 1.53-2.15). CONCLUSION: Sibling fracture history is associated with increased MOF risk and should be considered as a candidate risk factor for improving fracture risk prediction.

Fracture prediction from FRAX for Canadian ethnic groups: a registry-based cohort study.

We identified large between-ethnicity calibration differences in the Canadian FRAX® tool which substantially overestimated the major osteoporotic fracture (MOF) risk in Asian women and Black women, and overestimated hip fracture risk in Asian women. PURPOSE: FRAX® is calibrated using population-specific fracture and mortality data. The need for FRAX to accommodate ethnic diversity within a country is uncertain. We addressed this question using the population-based Manitoba Bone Mineral Density (BMD) Program registry and self-reported ethnicity. METHODS: The study population was women aged 40 years or older with baseline FRAX assessments (Canadian and other ethnic calculators), fracture outcomes, and self-reported ethnicity (White N = 68,907 [referent], Asian N = 1910, Black N = 356). Adjusted hazard ratios (HR) with 95% confidence intervals (CI) for time to MOF and hip fracture were estimated. We examined candidate variables from DXA that might contribute to ethnic differences including skeletal size, hip axis length (HAL), trabecular bone score (TBS), and estimated body composition. RESULTS: Adjusted for baseline risk using the Canadian FRAX tool with BMD, Asian women compared with White women were at much lower risk for MOF (HR 0.46, 95% CI 0.35-0.59) and hip fracture (0.16, 95% CI 0.08-0.34). Black women were also at lower MOF risk (HR 0.58, 95% CI 0.32-1.00); there were no hip fractures. The US ethnic-specific FRAX calculators accounted for most of the between-ethnicity differences in MOF risk (86% for Asian, 92% for Black) but only partially accounted for lower hip fracture risk in Asian women (40%). The candidate variables explained only a minority of the effect of ethnicity. Gradient of risk in analyses was similar (p-interactions ethnicity*FRAX non-significant). CONCLUSIONS: We identified significant ethnic differences in performance of the Canadian FRAX tool with fracture probability overestimated among Asian and Black women. The US ethnic calculators helped to address this discrepancy for MOF risk assessment, but not for hip fracture risk among Asian women.

Differences in fracture prevalence and in bone mineral density between Chinese and White Canadians: the Canadian Multicentre Osteoporosis Study (CaMos).

Fracture determinants differ between Canadians of Chinese and White descent, the former constituting the second largest visible minority group in Canada. The results of this study support the importance of characterizing bone health predictors in Canadians of different ethnicity to improve population-specific fracture prevention and treatment strategies. PURPOSE: We aimed to compare clinical risk factors, bone mineral density, prevalence of osteoporosis, and fractures between Chinese and White Canadians to identify ethnicity-specific risks. METHODS: We studied 236 Chinese and 8945 White Canadians aged 25+ years from the Canadian Multicentre Osteoporosis Study (CaMos). The prevalence of osteoporosis using ethnicity-specific peak bone mass (PBM), and of prior and incident low trauma fractures were assessed and compared between groups. Linear regressions, adjusting for age and anthropometric measures, were used to examine the association between baseline and 5-year changes in BMD and ethnicity. RESULTS: Chinese participants had shorter stature, lower BMI, and lower rate of falls than White participants. Adjusted models showed no significant differences in baseline BMD between ethnic groups except in younger men where total hip BMD was 0.059 g/cm2 (0.009; 0.108) lower in Chinese. Adjusted 5-year BMD change at lumbar spine was higher in older Chinese women and men compared with Whites. When using Chinese-specific PBM, the prevalence of osteoporosis in Chinese women was 2-fold lower than when using that of White women The prevalence of fractures was higher in White women compared with Chinese with differences up to 14.5% (95% CI 9.2; 19.7) and 10.5% (95% CI 4.5-16.4) in older White men. Incident fractures were rare in young Chinese compared with White participants and not different in the older groups. CONCLUSION: Our results support the importance of characterizing bone strength predictors in Chinese Canadians and the development of ethnicity-specific fracture prediction and prevention strategies.

Frequency of normal bone measurement in postmenopausal women with fracture: a registry-based cohort study.

This registry-based cohort study assessed the percentage of women with prior or incident fracture who had normal bone defined as a normal bone mineral density T-score and normal trabecular bone score (TBS). Inclusion of TBS reduced the percentage with normal bone. Normal bone measurement is rare in women with fracture. INTRODUCTION: Some fractures occur in women with normal BMD. We hypothesized that adding trabecular bone score (TBS) to DXA would (1) demonstrate that few women with fracture have normal bone, i.e., normal BMD T-score and TBS and (2) increase the percentage of women with fracture that have abnormal bone defined as a BMD T-score ≤ - 2.5 or low TBS. METHODS: The public healthcare system in Manitoba, Canada, makes it possible to link clinical DXA data to population databases. This study included all women age 50+ with a first DXA from February 1999 to March 2018 with valid BMD, TBS, and fracture data. Bone status was defined as Normal = BMD T-score of the spine, femoral neck, and total femur ≥ - 1.0 AND TBS > 1.31; Abnormal = BMD T-score ≤ - 2.5 OR TBS < 1.23; and borderline = all others. Analyses were stratified by age decade. RESULTS: Among women with prior (n = 4649) or incident (n = 2547) fracture, bone status assessed by both BMD and TBS was normal in only 6% and 4%, respectively. In women with prior or incident hip fracture, normal bone was present in < 1%. The prevalence of normal bone declined (p trend < 0.001) with age as expected. BMD T-score osteoporosis was present in 40% with any prior and 46% with any incident fracture. BMD T-score osteoporosis was present in 65% and 60% with prior and incident hip fracture, respectively. Including TBS with BMD increased the percentage of women with abnormal bone to 61% and 68% for any prior or incident fracture and to 80% and 81% for prior or incident hip fracture, respectively (all p < 0.001). CONCLUSION: Including TBS with BMD increases identification of abnormal bone in women with fracture compared with BMD alone. Normal bone is present in < 6% of women with any fracture and < 1% of those with hip fracture. What is thought to be normal bone in women with fracture is rarely normal.

Varying levels of serum estradiol do not alter the timing of the early endometrial secretory transformation.

STUDY QUESTION: Do supraphysiologic estradiol (E2) levels in the ranges attained during normal and high response superovulation cycles modify the onset of endometrial secretory transformation? SUMMARY ANSWER: Highly supraphysiologic levels of E2 do not alter the ability of physiologic levels of progesterone (P4) to induce secretory transformation. WHAT IS KNOWN ALREADY: Previous studies have demonstrated that premature P4 elevations during IVF cycles are associated with a decrement in clinical pregnancy rates after fresh embryo transfer due to shifts in the window of implantation (WOI). However, alterations in the onset of secretory transformation may not apply uniformly to all patients. High responders with supraphysiologic E2 levels accompanied by similar subtle increases in P4 have not been shown to have decreased sustained implantation rates. This prospective investigation in which whole-genome transcriptomic and methylomic analysis of the endometrium is performed for individual patients under a range of E2 concentrations brings clarity to a long-debated issue. STUDY DESIGN, SIZE, DURATION: A randomized, prospective and paired trial was conducted in which 10 participants were enrolled and randomized to the order in which they completed three distinct uterine stimulation cycles, each at a specific E2 concentration: physiologic (∼180 pg/ml), moderately supraphysiologic (600-800 pg/ml) or supraphysiologic (2000 pg/ml). Target E2 ranges were selected to mimic those seen in natural, controlled ovarian stimulation and IVF cycles. E2 valerate was administered in order to maintain stable E2 levels for 12 days followed by intramuscular P4 in oil 10 mg/day for two doses, after which an endometrial biopsy was performed. A total of 30 endometrial biopsies were included in a whole-genome transcriptomic and methylomic analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthy volunteers without a history of infertility were included in this study at a single large infertility center. DNA was isolated from the endometrial biopsy specimens and bisulfite sequencing was performed to construct a methylation array. Differential methylation analysis was conducted based on differences in M-values of individuals across treatment groups for each probe as well as carrying out t-tests. RNA was isolated for RNA-Seq analysis and gene expression values were compared using DESeq2. All analyses were performed in a pairwise fashion to compare among the three stimulation cycles within individuals and secondarily to compare all participants in each of the cycles. MAIN RESULTS AND THE ROLE OF CHANCE: The mean peak E2 and P4 levels were 275 pg/ml and 4.17 ng/ml in the physiologic group, 910 pg/ml and 2.69 ng/ml in the moderate group was, and 2043 pg/ml and 2.64 ng/ml in the supraphysiologic group, respectively. Principal component analysis of 834 913 CpG sites was performed on M-values of individuals within the low, moderate and supraphysiologic conditions in a paired approach. There were no differences in genome-wide methylation within participants across E2 groups. A paired analysis revealed that gene expression profiles did not differ within the same individual at each of the three E2 levels. No significant alterations in gene expression as related to endometrial physiology were identified between the low, moderate and supraphysiologic groups in an inter-participant analysis. LIMITATIONS, REASONS FOR CAUTION: Although each participant completed a physiologic cycle in which E2 levels were maintained in a range that would simulate a natural cycle, our findings are limited by lack of an unmedicated control to assess if there was a potential effect from E2V. Additionally, our results were obtained in fertile individuals, who may have a different endometrial response compared to an infertile population. Despite the whole genomic endometrial assessment and rigorous, paired study design, the sample size was limited. WIDER IMPLICATIONS OF THE FINDINGS: Given that the endometrial response to P4 is unaffected by E2 levels in the supraphysiologic range, diminutions in implantation seen in stimulated cycles may result from embryonic-endometrial dyssynchrony following early P4 elevations or slowly blastulating embryos, which occur independently of the magnitude of the E2 rise. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Foundation for Embryonic Competence, Basking Ridge, NJ, USA. Dr E.S. reports consultancy work for The Foundation for Embryonic Competence, Basking Ridge, NJ, USA. The other authors declare no conflict of interests related to this topic. TRIAL REGISTRATION NUMBER: NCT02458404.

Core principles for fracture prevention: North American Consensus from the National Osteoporosis Foundation, Osteoporosis Canada, and Academia Nacional de Medicina de Mexico.

Core principles for fracture prevention address fundamental concepts for the evaluation and management of patients at risk for fracture. These are intended to form the foundation of clinical practice guidelines and represent a first step toward guideline harmonization. INTRODUCTION: The large number of clinical practice guidelines for osteoporosis and discordance of recommendations has led to confusion among clinicians and patients, and likely contributes to the large osteoporosis treatment gap. We propose that stakeholder organizations reach agreement on fundamental principles in the management of osteoporosis and prevention of fracture as a first step toward a goal of guideline harmonization. METHODS: The best available evidence, as interpreted by an ad hoc working group of expert representatives from major osteoporosis societies in North America, was considered in the development of core principles for skeletal healthcare. These principles were subsequently endorsed by the USA National Osteoporosis Foundation, Osteoporosis Canada, and Academia Nacional de Medicina de Mexico (National Academy of Medicine of Mexico). RESULTS: Core principles are summarized here in bullet format. Categories include evaluation, lifestyle and nutrition, pharmacological therapy, and monitoring. A pathway forward to achieve guideline harmonization, at least in part, is proposed. CONCLUSION: Greater concordance of recommendations for the care of patients at risk for fracture are expected to lead to improved patient care across jurisdictions, with a narrowing of the osteoporosis treatment gap and reduced burden of fractures.