Previous fracture and subsequent fracture risk: a meta-analysis to update FRAX.

A large international meta-analysis using primary data from 64 cohorts has quantified the increased risk of fracture associated with a previous history of fracture for future use in FRAX. INTRODUCTION: The aim of this study was to quantify the fracture risk associated with a prior fracture on an international basis and to explore the relationship of this risk with age, sex, time since baseline and bone mineral density (BMD). METHODS: We studied 665,971 men and 1,438,535 women from 64 cohorts in 32 countries followed for a total of 19.5 million person-years. The effect of a prior history of fracture on the risk of any clinical fracture, any osteoporotic fracture, major osteoporotic fracture, and hip fracture alone was examined using an extended Poisson model in each cohort. Covariates examined were age, sex, BMD, and duration of follow-up. The results of the different studies were merged by using the weighted ß-coefficients. RESULTS: A previous fracture history, compared with individuals without a prior fracture, was associated with a significantly increased risk of any clinical fracture (hazard ratio, HR = 1.88; 95% CI = 1.72-2.07). The risk ratio was similar for the outcome of osteoporotic fracture (HR = 1.87; 95% CI = 1.69-2.07), major osteoporotic fracture (HR = 1.83; 95% CI = 1.63-2.06), or for hip fracture (HR = 1.82; 95% CI = 1.62-2.06). There was no significant difference in risk ratio between men and women. Subsequent fracture risk was marginally downward adjusted when account was taken of BMD. Low BMD explained a minority of the risk for any clinical fracture (14%), osteoporotic fracture (17%), and for hip fracture (33%). The risk ratio for all fracture outcomes related to prior fracture decreased significantly with adjustment for age and time since baseline examination. CONCLUSION: A previous history of fracture confers an increased risk of fracture of substantial importance beyond that explained by BMD. The effect is similar in men and women. Its quantitation on an international basis permits the more accurate use of this risk factor in case finding strategies.

Infrared spectroscopy is suitable for objective assessment of articular cartilage health.

Objective: To evaluate the feasibility of Fourier transform infrared attenuated total reflectance (FTIR-ATR) spectroscopy to detect cartilage degradation due to osteoarthritis and to validate the methodology with osteochondral human cartilage samples for future development towards clinical use. Design: Cylindrical (d â€‹= â€‹4 â€‹mm) osteochondral samples (n â€‹= â€‹349) were prepared from nine human cadavers and measured with FTIR-ATR spectroscopy. Afterwards, the samples were assessed with Osteoarthritis Research Society International (OARSI) osteoarthritis cartilage histopathology assessment system and divided into two groups: 1) healthy (OARSI 0-2) and 2) osteoarthritic (OARSI 2.5-6). The classification was done with partial least squares discriminant analysis model utilizing cross-model validation. Receiver operating characteristics curve analysis was performed and the area under curve (AUC) was calculated. Results: For all samples combined, classification accuracy was 73% with AUC of 0.79. Femoral samples had accuracy of 74% and AUC of 0.77, while tibial samples had accuracy of 66%, and AUC of 0.74. Patellar samples had accuracy of 84% and AUC of 0.91. Conclusions: The results indicate that FTIR-ATR spectroscopy can differentiate between healthy and osteoarthritic femoral, tibial and patellar human tissue. If combined with a fiber optic probe, FTIR-ATR spectroscopy could provide additional objective intraoperative information during arthroscopic surgeries, which could improve clinical outcomes.

Update of the fracture risk prediction tool FRAX: a systematic review of potential cohorts and analysis plan.

We describe the collection of cohorts together with the analysis plan for an update of the fracture risk prediction tool FRAX with respect to current and novel risk factors. The resource comprises 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. INTRODUCTION: The availability of the fracture risk assessment tool FRAX® has substantially enhanced the targeting of treatment to those at high risk of fracture with FRAX now incorporated into more than 100 clinical osteoporosis guidelines worldwide. The aim of this study is to determine whether the current algorithms can be further optimised with respect to current and novel risk factors. METHODS: A computerised literature search was performed in PubMed from inception until May 17, 2019, to identify eligible cohorts for updating the FRAX coefficients. Additionally, we searched the abstracts of conference proceedings of the American Society for Bone and Mineral Research, European Calcified Tissue Society and World Congress of Osteoporosis. Prospective cohort studies with data on baseline clinical risk factors and incident fractures were eligible. RESULTS: Of the 836 records retrieved, 53 were selected for full-text assessment after screening on title and abstract. Twelve cohorts were deemed eligible and of these, 4 novel cohorts were identified. These cohorts, together with 60 previously identified cohorts, will provide the resource for constructing an updated version of FRAX comprising 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. For each known and candidate risk factor, multivariate hazard functions for hip fracture, major osteoporotic fracture and death will be tested using extended Poisson regression. Sex- and/or ethnicity-specific differences in the weights of the risk factors will be investigated. After meta-analyses of the cohort-specific beta coefficients for each risk factor, models comprising 10-year probability of hip and major osteoporotic fracture, with or without femoral neck bone mineral density, will be computed. CONCLUSIONS: These assembled cohorts and described models will provide the framework for an updated FRAX tool enabling enhanced assessment of fracture risk (PROSPERO (CRD42021227266)).

Regional and gender-specific analyses give new perspectives for secular trend in hip fracture incidence.

In this study, we found that regional disparity in incidence of hip fractures has converged. Also, annual hip fracture risk ratios between genders have systematically diminished over time. INTRODUCTION: Several studies have reported secular trends in hip fracture incidence, but knowledge about the possible causes is limited. We studied potential explanations by examining spatio-temporal epidemiology of the fractures and estimating relative risks between genders. METHODS: This observational study was based on all inpatient hospital discharges in 1972-2018 in Finland. We divided the data by gender, 5-year age groups and Finnish sub-regions and estimated gender and age standardized spatio-temporal rates of hip fractures by using a Bayesian age-period-cohort model. RESULTS: In 1972, women's hip fracture incidence was 1.2-1.3 times higher in western and coastal Finland compared to eastern and inland areas. Also, women had approximately 1.7 times higher average risk to get a hip fracture compared to men. Today, the hip fracture differences between the areas have converged to insignificant and the relative risk between genders has diminished to 1.2. Age-specific relative risks indicate greater hip fracture risk for younger men and older women, and the women's risk increases beyond the risk of men at age 65 which is ten years later than in the beginning of the study period. CONCLUSION: Incidence of hip fracture has converged significantly between regions and genders. Especially factors related with socioeconomic development and increased frailty and longevity seem to be important. The hip fracture incidence rate ratio between women and men has systematically decreased in time, and more attention should be paid to hip fracture risk in men in the future.

Obesity is associated with early hip fracture risk in postmenopausal women: a 25-year follow-up.

Association of body mass index and hip fracture has been controversial. In this study, women with lowest and highest body weight had the highest fracture incidence. A 25-year follow-up indicated that obesity associates with early hip fracture risk and suggested increasing trend in normal-weight women at a later stage. INTRODUCTION: Obesity is a pandemic health issue. Its association with hip fracture risk remains controversial. We studied the long-term relationship of body mass index and hip fracture incidence in postmenopausal women. METHODS: The cohort of 12,715 Finnish women born in 1932-1941 was followed for 25 years, covering ages from 58 up to 83. Fractures and deaths were obtained from national registries. Women were investigated in deciles of BMI as well as in WHO weight categories (normal, overweight, or obese). The follow-up analysis was carried out in two age strata as "early" (58-70 years) and "late" (> 70 years). Body weight information was updated accordingly. Femoral neck BMD was recorded for a subsample (n = 3163). Altogether, 427 hip fractures were observed. RESULTS: A higher risk of early hip fracture was observed in obese and normal-weight compared with overweight women with hazard ratios (HRs) of 2.3 ((95% CI) 1.4-3.7) and 2.0 (1.3-3.1) while no difference was observed in late hip fracture risk between the three WHO categories (log rank p = 0.14). All-cause mortality during the follow-up was 19.3%. Compared with normal weight women, the obese women had a higher risk of death with an HR of 1.6 (1.4-1.8) and higher baseline BMD (p < 0.001). Faster bone loss was observed in the obese compared with other women (p < 0.001). CONCLUSION: Obesity associates with earlier hip fracture and higher postfracture mortality. The obese women with low BMD have clearly the highest risk of hip fracture. This combination increases hip fracture risk more than either of the factors alone. After 75 years of age, risk appears to increase more in normal weight women, but this trend is in need of further confirmation.

Automating three-dimensional osteoarthritis histopathological grading of human osteochondral tissue using machine learning on contrast-enhanced micro-computed tomography.

OBJECTIVE: To develop and validate a machine learning (ML) approach for automatic three-dimensional (3D) histopathological grading of osteochondral samples imaged with contrast-enhanced micro-computed tomography (CEµCT). DESIGN: A total of 79 osteochondral cores from 24 total knee arthroplasty patients and two asymptomatic donors were imaged using CEµCT with phosphotungstic acid -staining. Volumes-of-interest (VOI) in surface (SZ), deep (DZ) and calcified (CZ) zones were extracted depth-wise and subjected to dimensionally reduced Local Binary Pattern -textural feature analysis. Regularized linear and logistic regression (LR) models were trained zone-wise against the manually assessed semi-quantitative histopathological CEµCT grades (diameter = 2 mm samples). Models were validated using nested leave-one-out cross-validation and an independent test set (4 mm samples). The performance was primarily assessed using Mean Squared Error (MSE) and Average Precision (AP, confidence intervals are given in square brackets). RESULTS: Highest performance on cross-validation was observed for SZ, both on linear regression (MSE = 0.49, 0.69 and 0.71 for SZ, DZ and CZ, respectively) and LR (AP = 0.9 [0.77-0.99], 0.46 [0.28-0.67] and 0.65 [0.41-0.85] for SZ, DZ and CZ, respectively). The test set evaluations yielded increased MSE on all zones. For LR, the performance was also best for the SZ (AP = 0.85 [0.73-0.93], 0.82 [0.70-0.92] and 0.8 [0.67-0.9], for SZ, DZ and CZ, respectively). CONCLUSION: We present the first ML-based automatic 3D histopathological osteoarthritis (OA) grading method which also adequately perform on grading unseen data, especially in SZ. After further development, the method could potentially be applied by OA researchers since the grading software and all source codes are publicly available.

Unfolding the outcomes of surgical treatment of lumbar spinal stenosis-a prospective 5- and 10-year follow-up study.

PURPOSE: In this prospective study, we aim to determine surgical outcomes in patients with lumbar spinal stenosis (LSS) 10 years after surgery. METHODS: The study population consisted of 96 LSS patients who underwent decompressive surgery, 72 of whom participated in the 10-year follow-up. The patients completed a questionnaire preoperatively and 3 months, 5 years, and 10 years postoperatively. Outcome measures were satisfaction with the surgical outcomes, the Oswestry Disability Index (ODI), the visual analog scale (VAS), the numeric rating scale (NRS-11), and walking ability quantified in meters. Postoperative improvements at 5 and 10 years were analyzed using linear mixed models. Furthermore, comparisons between postoperative time points were made for clinical courses of pain, disability, and walking ability. RESULTS: At the 10-year follow-up, 68% of the patients were satisfied with the surgical outcomes. All the measured outcomes showed statistically significant improvement from baseline to the 5- and 10-year follow-up. The mean VAS score was 9.8 mm higher at the 5-year follow-up and 7.8 mm at the 10-year follow-up compared to the 3-month follow-up point. Similarly, the mean ODI was 4.8% higher at the 10-year follow-up compared to the 3-month follow-up point. CONCLUSION: This study reports the clinical course of pain, disability, and walking distance after LSS surgery with the 10-year follow-up. Based on our study results, patients with LSS could expect to have positive effects of their back surgery up to 10 years. However, minor worsening in pain and disability may occur and one-fourth of the patients may need a reoperation during the 10-year follow-up period.

Quantifying Subresolution 3D Morphology of Bone with Clinical Computed Tomography.

The aim of this study was to quantify sub-resolution trabecular bone morphometrics, which are also related to osteoarthritis (OA), from clinical resolution cone beam computed tomography (CBCT). Samples (n = 53) were harvested from human tibiae (N = 4) and femora (N = 7). Grey-level co-occurrence matrix (GLCM) texture and histogram-based parameters were calculated from CBCT imaged trabecular bone data, and compared with the morphometric parameters quantified from micro-computed tomography. As a reference for OA severity, histological sections were subjected to OARSI histopathological grading. GLCM and histogram parameters were correlated to bone morphometrics and OARSI individually. Furthermore, a statistical model of combined GLCM/histogram parameters was generated to estimate the bone morphometrics. Several individual histogram and GLCM parameters had strong associations with various bone morphometrics (|r| > 0.7). The most prominent correlation was observed between the histogram mean and bone volume fraction (r = 0.907). The statistical model combining GLCM and histogram-parameters resulted in even better association with bone volume fraction determined from CBCT data (adjusted R2 change = 0.047). Histopathology showed mainly moderate associations with bone morphometrics (|r| > 0.4). In conclusion, we demonstrated that GLCM- and histogram-based parameters from CBCT imaged trabecular bone (ex vivo) are associated with sub-resolution morphometrics. Our results suggest that sub-resolution morphometrics can be estimated from clinical CBCT images, associations becoming even stronger when combining histogram and GLCM-based parameters.

A fall in the previous 12 months predicts fracture in the subsequent 5 years in postmenopausal women.

PURPOSE: The purpose of this study was to evaluate if a history of falls predicts future postmenopausal fractures and if this prediction variesaccording to frequency, mechanism, and severity of falls and site of fractures. METHODS: This study used data from OSTPRE prospective cohort. Total study population consisted of 8744 postmenopausal women (mean age 62.2 years) who responded to postal enquiry in 1999 (baseline) and in 2004 (follow-up). RESULTS: Women were classified by frequency (non/occasional/frequent fallers), mechanism (slip/nonslip), and severity (injurious/ non-injurious) of falls and fractures by site (major osteoporotic/other). A total of 1693 (19.4%) women reported a fall during the preceding 12 months in 1999; 812 a slip fall, 654 a nonslip, 379 an injurious fall, and 1308 a non-injurious fall. A total of 811 women (9.3%) sustained a fracture during the 5-year follow-up period (1999-2004); 431 major osteoporotic fractures and 380 other fractures. Compared with non-fallers, earlier falls predicted subsequent fractures with an OR of 1.41 (95% CI 1.19-1.67, p ≤ 0.001), 1.43 (95% CI 1.14-1.80, p = 0.002) for earlier slip falls, and 1.35 (95% CI 1.04-1.74, p = 0.02) for earlier nonslip falls. Earlier injurious falls predicted future fractures (OR = 1.64, 95% CI 1.21-2.23, p ≤ 0.01), especially other fractures (OR = 1.86, 95% CI 1.24-2.80, p ≤ 0.01), but not major osteoporotic fractures (OR = 1.37, 95% CI 0.89-2.10, p = 0.151). Fracture risk predictions for earlier non-injurious falls was OR = 1.36, 95% CI 1.12-1.64, p = 0.002. These risk patterns remain same after adjustments. CONCLUSION: History of falls (especially injurious falls) predicts subsequent fractures (mainly other fractures compared with major osteoporotic fractures) inpostmenopausal women. We aimed to investigate if history of falls (frequency, mechanism, and severity) is a predictor of future fractures in postmenopausal women. Our results indicate that history of falls (especially injurious falls) appeared to be an indicator for subsequent fracture overall. Earlier injurious falls were stronger predictors for future other fractures than for typical major osteoporotic fractures.

Long-term thiazide use and risk of low-energy fractures among persons with Alzheimer's disease-nested case-control study.

We investigated the association between thiazide use and the risk of low-energy fractures among community dwellers with Alzheimer's disease. Longer use was associated with a decreased risk of low-energy fractures. This study extends the previous knowledge of reduced fracture risk of thiazides to persons with Alzheimer's disease. INTRODUCTION: To investigate the association between thiazide use and the risk of low-energy fractures (LEF), and hip fracture among community dwellers with Alzheimer's disease (AD). No prior study has evaluated the effect of thiazides on LEF risk of AD patients. METHODS: LEF cases were identified from the MEDALZ study, including all community-dwelling persons diagnosed with AD in Finland 2005-2011. During the follow-up from AD diagnoses until the end of 2015, cases with LEF (N = 10,416) and hip fracture (N = 5578) were identified. LEF cases were matched with up to three controls without LEF, according to time since AD diagnosis, age and gender. Thiazide use identified from the Prescription register data was modeled with PRE2DUP method. Current use was defined in 0-30 days' time window before the fracture/matching date, and duration of current use was assessed. The association between thiazide exposure and LEFs was assessed with conditional logistic regression. RESULTS: Current thiazide use was observed in 10.5% of LEF cases and 12.5% of controls. Current thiazide use was associated with a decreased risk of LEF (adjusted OR [aOR] 0.83, 95% CI 0.77-0.88). In terms of the duration of use, no association was observed with short-term use (< 1 year or 1-3 years), while longer use (> 3 years) was associated with a reduced risk of LEF (aOR 0.77, 95% CI 0.71-0.83) and hip fracture (aOR 0.68, 95% CI 0.60-0.78). CONCLUSIONS: Our study extends the previous knowledge of reduced fracture risk of thiazides to persons with AD, a population with significantly increased background risk of fractures.

Near-infrared spectroscopy enables quantitative evaluation of human cartilage biomechanical properties during arthroscopy.

OBJECTIVE: To investigate the feasibility of near-infrared (NIR) spectroscopy (NIRS) for evaluation of human articular cartilage biomechanical properties during arthroscopy. DESIGN: A novel arthroscopic NIRS probe designed in our research group was utilized by an experienced orthopedic surgeon to measure NIR spectra from articular cartilage of human cadaver knee joints (ex vivo, n = 18) at several measurement locations during an arthroscopic surgery. Osteochondral samples (n = 265) were extracted from the measurement sites for reference analysis. NIR spectra were remeasured in a controlled laboratory environment (in vitro), after which the corresponding cartilage thickness and biomechanical properties were determined. Hybrid multivariate regression models based on principal component analysis and linear mixed effects modeling (PCA-LME) were utilized to relate cartilage in vitro spectra and biomechanical properties, as well as to account for the spatial dependency. Additionally, a k-nearest neighbors (kNN) classifier was employed to reject outlying ex vivo NIR spectra resulting from a non-optimal probe-cartilage contact. Model performance was evaluated for both in vitro and ex vivo NIR spectra via Spearman's rank correlation (ρ) and the ratio of performance to interquartile range (RPIQ). RESULTS: Regression models accurately predicted cartilage thickness and biomechanical properties from in vitro NIR spectra (Model: 0.77 ≤ ρ ≤ 0.87, 2.03 ≤ RPIQ ≤ 3.0; Validation: 0.74 ≤ ρ ≤ 0.84, 1.87 ≤ RPIQ ≤ 2.90). When predicting cartilage properties from ex vivo NIR spectra (0.33 ≤ ρ ≤ 0.57 and 1.02 ≤ RPIQ ≤ 2.14), a kNN classifier enhanced the accuracy of predictions (0.52 ≤ ρ ≤ 0.87 and 1.06 ≤ RPIQ ≤ 1.88). CONCLUSION: Arthroscopic NIRS could substantially enhance identification of damaged cartilage by enabling quantitative evaluation of cartilage biomechanical properties. The results demonstrate the capacity of NIRS in clinical applications.

Role of musculoskeletal disorders in falls of postmenopausal women.

We aimed to investigate the role of musculoskeletal disorders (MSDs) as risk factors for falls among postmenopausal women. Our results indicate that MSDs are common and are associated with increased falling risk, especially nonslip falls. Excess number of falls due to MSDs is greater than that due to any other disease class. PURPOSE: Falls are a major public health problem worldwide. The aim of the study was to investigate the role of MSDs as risk factors for falls among postmenopausal women. METHODS: This cohort study utilized data from a population-based, prospective cohort study (OSTPRE). The study population consisted of 8656 women aged 57-66 years (in 1999) living in Kuopio Province, Eastern Finland, who responded to postal enquiries in 1999 and 2004. Information on MSDs and other morbidities was obtained from the 1999 enquiry and information on falls from the 2004 enquiry. Women were classified as fallers or non-fallers according to their falling events in the preceding 12 months. The fallers were further divided into women with slip and nonslip falls. RESULTS: Of the study sample, 53.3% reported a MSD and 39.2% reported a fall during the preceding 12 months. MSDs predicted falls (OR = 1.38; 95% CI 1.26-1.50) and the association was stronger for nonslip (OR = 1.56; 95% CI 1.39-1.75) than slip falls (OR 1.22; 95% CI 1.08-1.38) compared to the women without MSDs. The risk of falls increased with increasing number (1, 2, ≥ 3) of MSDs: 1.25 (95%CI 1.13-1.38), 1.48 (95%CI 1.30-1.68), and 1.92 (95%CI 1.60-2.31), respectively. After adjustments, the risk of falling related to MSDs reduced by about 5% (adjusted p < 0.001). The population attributable fraction of falls due to MSDs was 10.3% of all falls, greater than that due to any other disease class. CONCLUSION: MSDs are common and an important risk factor for falls and especially nonslip falls among postmenopausal women. The number of excess falls due to MSDs in this population group is greater than that due to any other disease class.

Long-term effects of functional impairment on fracture risk and mortality in postmenopausal women.

Our findings imply that simple functional tests can predict both hip fracture risk and excess mortality in postmenopausal women. Since the tests characterize general functional capacity (one-legged stance, squatting down, and grip strength), these simple measures should have clinical utility in the assessment of women at risk of falls and fragility fracture. INTRODUCTION: Functional impairment is associated with the risk of fall, which is the leading cause of hip fracture. We aimed to determine how clinical assessments of functional impairment predict long-term hip fracture and mortality. METHODS: A population-based prospective cohort involved 2815 Caucasian women with the average baseline age of 59.1 years. The mean follow-up time in 1994-2014 was 18.3 years. Three functional tests and their combinations assessed at baseline were treated as dichotomous risk factors: (1) inability to squat down and touch the floor (SQ), (2) inability to stand on one leg for 10 s (SOL), and (3) having grip strength (GS) within the lowest quartile (≤ 58 kPa, mean 45.6 kPa). Bone mineral density (BMD) at the proximal femur was measured by DXA. Fractures and deaths were verified from registries. Hazard ratios were determined by using Cox proportional models. Age, body mass index (BMI), and BMD were included as covariates for fracture risk estimates. Age, BMI, and smoking were used for mortality. RESULTS: Altogether, 650 (23.1%) women had 718 follow-up fractures, including 86 hip fractures. The mortality during the follow-up was 16.8% (n = 473). Half of the women (56.8%, n = 1600) had none of the impairments and were regarded as the referent group. Overall, women with any of the three impairments (43.2%, n = 1215) had higher risks of any fracture, hip fracture, and death, with hazard ratios (HR) of 1.3 ((95% CI) 1.0-1.5, p < 0.01), 2.4 (1.5-3.4, p < 0.001), and 1.5 (1.3-1.8, p < 0.001), respectively. The strongest single predictor for hip fracture was failing to achieve a one-leg stand for 10 s (prevalence 7.1%, n = 200), followed by inability to squat down (27.0%, n = 759) and weak grip strength (24.4%, n = 688), with their respective HRs of 4.3 (2.3-8.0, p < 0.001), 3.1 (2.0-5.0, p < 0.001), and 2.0 (1.2-3.4, p < 0.001). In addition, age, lower BMD, BMI, and smoking were significant covariates. CONCLUSIONS: These findings suggest that functional tests provide long-term prediction of fracture and death in postmenopausal women. Whether reversal of these impairments is associated with a reduction in adverse outcomes is an area for future trials.

Pulse-echo ultrasound method for detection of post-menopausal women with osteoporotic BMD.

We lack effective diagnostics of osteoporosis at the primary health care level. An ultrasound device was used to identify subjects in the osteoporotic range as defined by DXA. A case finding strategy combining ultrasound results with DXA measurements for patients with intermediate ultrasound results is presented. INTRODUCTION: We lack effective screening and diagnostics of osteoporosis at primary health care. In this study, a pulse-echo ultrasound (US) method is investigated for osteoporosis screening. METHODS: A total of 1091 Caucasian women (aged 50-80 years) were recruited for the study and measured with US in the tibia and radius. This method measures cortical thickness and provides an estimate of bone mineral density (BMD) and density index (DI). BMD assessment of the hip was available for 988 women. A total of 888 women had one or more risk factors for osteoporosis (OP susp ), and 100 women were classified healthy. Previously determined thresholds for the DI were evaluated for assessment of efficacy of the technique to detect hip BMD at osteoporotic range (T-score at or below - 2.5). RESULTS: In the OP susp group, the application of thresholds for the DI showed that approximately 32% of the subjects would require an additional DXA measurement. The multi-site ultrasound (US) measurement-based DI showed 93.7% sensitivity and 81.6% specificity, whereas the corresponding values for single-site US measurement-based DI were 84.7 and 82.0%, respectively. The ultrasound measurements showed a high negative predictive value 97.7 to 99.2% in every age decade examined (ages 50-59, 60-69, 70-79 years). CONCLUSIONS: The study data demonstrate that a strategy of combining ultrasound measurement with added DXA measurements in cases with intermediate ultrasound results (about 30%) can be useful for identifying subjects at risk for a low bone mineral density in the osteoporotic range.

Relationship of body anthropometric measures with skeletal muscle mass and strength in a reference cohort of young Finnish women.

OBJECTIVES: 1) To study if limb length explains variability in appendicular and total muscle mass better than height and 2) if muscle mass adjusted for limb length rather than height correlates better with grip and knee extension strength. METHODS: 400 healthy women aged 20-40 were recruited as a reference population. Body composition, limb length, grip strength and knee extension strength were measured. New relative muscle mass indexes were computed by adjusting upper limb muscle mass for upper limb length (ULRSMI) and lower limb muscle mass for lower limb length (LLRSMI). RESULTS: Height correlated strongest with all muscle mass measures. Height had the highest R² values for predicting variability in appendicular skeletal muscle mass (0.33), upper limb skeletal muscle mass (0.20), lower limb skeletal muscle mass (0.34) and total skeletal muscle mass (0.36). Correlation of relative skeletal muscle mass index (RSMI) with grip and knee extension strength (r=0.47 and 0.43) was higher when compared with correlation of ULRSMI and LLRSMI with these measures. CONCLUSION: Compared to limb length, height correlates better with regional and total muscle mass. Muscle mass adjusted for height correlates better with grip strength and knee strength when compared with muscle mass adjusted for limb length.

PLS3 sequencing in childhood-onset primary osteoporosis identifies two novel disease-causing variants.

Altogether 95 children with primary bone fragility were screened for variants in PLS3, the gene underlying X-linked osteoporosis. Two children with multiple peripheral and spinal fractures and low BMD had novel disease-causing PLS3 variants. Children with milder phenotypes had no pathogenic variants. PLS3 screening is indicated in childhood-onset primary osteoporosis. INTRODUCTION: The study aimed to determine the role of pathogenic PLS3 variants in children's bone fragility and to elucidate the associated phenotypic features. METHODS: Two cohorts of children with bone fragility were screened for variants in PLS3, the gene underlying X-linked osteoporosis. Cohort I comprised 31 patients with childhood-onset primary osteoporosis of unknown etiology. Cohort II comprised 64 children who had sustained multiple fractures but were otherwise healthy. Clinical and radiological data were reviewed. Peripheral blood DNA was Sanger sequenced for coding exons and flanking intronic regions of PLS3. RESULTS: In two patients of cohort I, where other common genetic causes had been excluded, we identified two novel disease-causing PLS3 variants. Patient 1 was a male with bilateral femoral fractures at 10 years, low BMD (Z-score -4.1; 18 years), and multiple vertebral compression fractures. He had a novel nonsense variant in PLS3. Patient 2 was a girl with multiple long bone and vertebral fractures and low BMD (Z-score -6.6 at 6 years). She had a de novo missense variant in PLS3; whole exome sequencing and array-CGH identified no other genetic causes. Iliac crest bone biopsies confirmed low-turnover osteoporosis in both patients. In cohort II, no pathogenic PLS3 variants were identified in any of the subjects. CONCLUSIONS: Two novel disease-causing variants in PLS3 were identified in a boy and a girl with multiple peripheral and spinal fractures and very low BMD while no pathogenic variants were identified in children with less severe skeletal fragility. PLS3 screening is warranted in male and female patients with childhood-onset primary osteoporosis.

Association of Protein Intake with Bone Mineral Density and Bone Mineral Content among Elderly Women: The OSTPRE Fracture Prevention Study.

It has been hypothesized that high protein intakes are associated with lower bone mineral content (BMC). Previous studies yield conflicting results and thus far no studies have undertaken the interaction of body mass index (BMI) and physical activity with protein intakes in relation to BMC and bone mineral density (BMD). OBJECTIVE: To evaluate the associations of dietary total protein (TP), animal protein (AP) and plant protein (PP) intakes with BMC and BMD and their changes. We tested also the interactions of protein intake with, obesity (BMI ≤30 vs. >30 kg/m2) and physical activity level (passive vs. active). Design/ Setting: Prospective cohort study (Osteoporosis Risk-Factor and Fracture-Prevention Study). Participants/measures: At the baseline, 554 women aged 65-72 years filled out a 3-day food record and a questionnaire covering data on lifestyle, physical activity, diseases, and medications. Intervention group received calcium 1000 mg/d and cholecalciferol 800 IU for 3 years. Control group received neither supplementation nor placebo. Bone density was measured at baseline and year 3, using dual energy x-ray absorptiometry. Multivariable regression analyses were conducted to examine the associations between protein intake and BMD and BMC. RESULTS: In cross-sectional analyses energy-adjusted TP (P≤0·029) and AP (P≤0·045) but not PP (g/d) were negatively associated with femoral neck (FN) BMD and BMC. Women with TP≥1·2 g/kg/body weight (BW) (Ptrend≤0·009) had lower FN, lumbar spine (LS) and total BMD and BMC. In follow-up analysis, TP (g/kg/BW) was inversely associated with LS BMD and LS BMC. The detrimental associations were stronger in women with BMI<30 kg/m2. In active women, TP (g/kg/BW) was positively associated with LS BMD and FN BMC changes. CONCLUSIONS: This study suggests detrimental associations between protein intake and bone health. However, these negative associations maybe counteracted by BMI>30 kg/m2 and physical activity.

Inclusion of Regional Body Composition Parameters Improves Bone Mineral Density Cross-Calibration Between GE Lunar Prodigy and iDXA Densitometers.

Since 1989, the Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE, n = 14220) Study has followed long-term changes of bone mineral density (BMD) and body composition in women with GE Lunar devices. During the course of OSTPRE, the dual-energy X-ray absorptiometry device had to be replaced by a newer model. Then, it was essential to determine whether systematic measurement differences in BMD and body composition will occur. As a part of the OSTPRE study, BMD was measured in 54 women, whereas body composition was determined in 55 women, aged 27-71, by using both the GE Healthcare Lunar Prodigy and iDXA narrow-angle fan beam densitometers during the same visit. The total body fat mass (FM) and lean body mass (LBM) results of these scanners showed a high linear correlation (r = 0.981-0.994, p < 0.0001). However, the mean total body FM and LBM values measured by iDXA were on average 2.3% (0.5 kg, 95% confidence interval: 0.3-0.7 kg) higher and 0.8% (0.3 kg, 95% confidence interval: 0.1-0.6 kg) lower, respectively, than those measured by Prodigy. Inclusion of local soft tissue measurements (total body LBM, legs/android FM) improved the agreement of total body, total hip, and lumbar spine BMD values between the devices but not femoral neck BMD agreement. Equations, based on linear regression analyses, were derived to minimize differences between the instruments. Then, the differences in BMD and body composition measurements were negligible between Prodigy and iDXA. Using correction equations enables an objective comparison of longitudinal BMD and body composition measurements.

Optimal graft stiffness and pre-strain restore normal joint motion and cartilage responses in ACL reconstructed knee.

Anterior cruciate ligament (ACL) rupture leads to abnormal loading of the knee joint and increases the risk of osteoarthritis. It is unclear how different ACL reconstruction techniques affect knee joint motion and mechanics. As the in vivo measurement of knee joint loading is not possible, we used finite element analysis to assess the outcome of ACL reconstruction techniques. Effects of different ACL reconstruction techniques on knee joint mechanics were studied using six models during gait; with 1) healthy ACL, 2) ACL rupture, 3) single bundle ACL reconstruction, 4) double bundle ACL reconstruction, 5) weakened (softer) single bundle reconstruction and 6) single bundle reconstruction with less pre-strain. Early in the gait, the ACL rupture caused substantially increased tibial translation in the anterior direction as well as a smaller but increased lateral translation and internal tibial rotation. ACL rupture substantially reduced average stresses and strains, while local peak stresses and strains could be either increased or decreased. Single bundle and double bundle reconstructions restored joint motion close to normal levels. However, cartilage strains and stresses were elevated during the entire gait cycle. Models with modulated graft stiffness and pre-strain restored the joint motion and cartilage stresses and strains close to the normal, healthy levels. Results suggest that rather than the choice of reconstruction technique, stiffness and pre-strain of the ACL reconstruction affect the motion and mechanics of the operated knee. We suggest that an optimal choice of graft properties might help restore normal knee joint function and cartilage responses, thus, minimizing the risk of osteoarthritis.